Lactam-containing compounds and derivatives thereof as factor Xa inhibitors

ABSTRACT

The present application describes lactam-containing compounds and derivatives thereof of Formula I: 
     P 4 -P-M-M 4    
     I 
     or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5–7 membered carbocycle or heterocycle and ring M is a 5–7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/245,122, filed Sep. 17, 2002, which claims the priority of U.S.Provisional Application No. 60/324,165, filed Sep. 21, 2001 and thepriority of U.S. Provisional Application No. 60/402,317, filed Aug. 9,2002, the contents of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates generally to lactam-containing compounds andderivatives thereof which are inhibitors of trypsin-like serine proteaseenzymes, especially factor Xa, pharmaceutical compositions containingthe same, and methods of using the same as anticoagulant agents fortreatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO94/20460 describes angiotensin II compounds of the following formula:

wherein X can be a number of substituents and Het can be anitrogen-containing heterobicycle. However, WO94/20460 does not suggestFactor Xa inhibition or exemplify compounds like those of the presentinvention.

WO96/12720 depicts phosphodiesterase type IV and TNF productioninhibitors of the following formula:

wherein X can be oxygen and R² and R³ can a number of substituentsincluding heterocycle, heterocycloalkyl, and phenyl. However, thepresently claimed compounds do not correspond to the compounds ofWO96/12720. Furthermore, WO96/12720 does not suggest Factor Xainhibition.

WO98/52948 details inhibitors of ceramide-mediated signal transduction.One of the types of inhibitors described is of the following formula:

wherein Y₁ can be N—R₆, R₆ can be unsubstituted aryl-alkyl orunsubstituted heterocyclic-alkyl and R₁ can be a substituted aryl group.WO98/52948 does not mention factor Xa inhibition or show compounds likethose of the present invention.

U.S. Pat. Nos. 3,365,459, 3,340,269, and 3,423,414 illustrateanti-inflammatory inhibitors of the following formula:

wherein A is 2–3 carbon atoms, X can be O, and R¹ and R³ can besubstituted or unsubstituted aromatic groups. Neither of these patents,however, exemplifies compounds of the present invention.

WO99/32477 reports Factor Xa inhibitors of the following formula:

wherein the inhibitors contain at least three aryl or heterocyclicgroups (i.e., C, B, and R³) separated by two linking groups (i.e., E andD). Compounds of this sort are not considered to be part of the presentinvention.

WO00/39131 describes heterobicyclic Factor Xa inhibitors of which thefollowing is an example formula:

wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclicmoiety and B is a basic group or a cyclic moiety. Compounds specificallydescribed in WO00/39131 are not considered to be part of the presentinvention.

WO98/28269, WO98/28282, WO99/32454, U.S. Pat. No. 6,020,357, and U.S.Pat. No. 6,271,237 describe Factor Xa inhibitors of the followingformula:

wherein ring M is a heterocycle, Z is a linker, A is a ring, B is abasic or cylic group, D is a basic moiety, and E is a ring. Compoundsspecifically described in WO98/28269, WO98/28282, WO99/32454, U.S. Pat.No. 6,020,357, and U.S. Pat. No. 6,271,237 are not considered to be partof the present invention.

WO98/57951 describes Factor Xa inhibitors of the following formula:

wherein ring M can be a variety of heterocycles and rings D-E representa heterobicyclic group. Compounds specifically described in WO98/57951are not considered to be part of the present invention.

WO98/57934 and U.S. Pat. No. 6,060,491 describe Factor Xa inhibitors ofthe following formula:

wherein ring M is a 6-membered heteroaryl, Z is a linker, A is a ring, Bis a basic or cylic group, D is a basic moiety, and E is a ring.Compounds specifically described in WO98/57934 and U.S. Pat. No.6,060,491 are not considered to be part of the present invention.

WO98/57937 and U.S. Pat. No. 5,998,424 describe Factor Xa inhibitors ofthe following formula:

wherein ring M is a variety of rings, ring D is an aromatic ring, and Rand E are non-basic groups. Compounds specifically described inWO98/57937 and U.S. Pat. No. 5,998,424 are not considered to be part ofthe present invention.

WO99/50255 and U.S. Pat. No. 6,191,159 describe pyrazoline andtriazoline Factor Xa inhibitors of the following formulas:

Compounds specifically described in WO99/50255 and U.S. Pat. No.6,191,159 are not considered to be part of the present invention.

WO00/59902 describes Factor Xa inhibitors of the following formula:

wherein ring M can be a variety of rings all of which are substitutedwith Z-A-B, Z is a linker, A is a ring, B is a sulfonyl-containingheterobicycle, and rings D-E represent a heterobicyclic group or a6-membered ring. Compounds specifically described in WO00/59902 are notconsidered to be part of the present invention.

WO01/32628 describes cyano-pyrroles, cyano-imidazoles, cyano-pyrazoles,and cyano-triazoles that are Factor Xa inhibitors. Compoundsspecifically described in WO01/32628 are not considered to be part ofthe present invention.

WO01/05784 describes Factor Xa inhibitors of the following formulas:

wherein Z is C or N, G is a mono- or bicyclic ring M, A is a linker, Bis a basic or cyclic group. Compounds specifically described inWO01/05784 are not considered to be part of the present invention.

WO00/39108 describes Factor Xa inhibitors of the following formula:

wherein ring M can be a variety of heterocycles and rings D-E representa heterobicyclic group. Compounds specifically described in WO00/39108are not considered to be part of the present invention.

WO01/19798 describes factor Xa inhibitors of the following formula:A-Q-D-E-G-J-Xwherein A, D, G, and X can be phenyl or heterocycle. However, none ofthe presently claimed compounds are exemplified or suggested inWO01/19798.

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617–629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors. In addition, it is also desirable to find new compounds withimproved pharmacological characteristics compared with known factor Xainhibitors. For example, it is preferred to find new compounds withimproved factor Xa inhibitory activity and selectivity for factor Xaversus other serine proteases (i.e., trypsin). It is also desirable andpreferable to find compounds with advantageous and improvedcharacteristics in one or more of the following categories, but are notlimited to: (a) pharmaceutical properties (e.g., solubility,permeability, and amenability to sustained release formulations); (b)dosage requirements (e.g., lower dosages and/or once-daily dosing); (c)factors which decrease blood concentration peak-to-troughcharacteristics (e.g., clearance and/or volume of distribution); (d)factors that increase the concentration of active drug at the receptor(e.g., protein binding, volume of distribution); (e) factors thatdecrease the liability for clinical drug—drug interactions (e.g.,cytochrome P450 enzyme inhibition or induction); (f) factors thatdecrease the potential for adverse side-effects (e.g., pharmacologicalselectivity beyond serine proteases, potential chemical or metabolicreactivity, and limited CNS penetration); and, (g) factors that improvemanufacturing costs or feasibility (e.g., difficulty of synthesis,number of chiral centers, chemical stability, and ease of handling).

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel lactam-containingcompounds and derivatives thereof that are useful as factor Xainhibitors or pharmaceutically acceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating thromboembolicdisorders comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides a novel method of treating a patient inneed of thromboembolic disorder treatment, comprising: administering acompound of the present invention or a pharmaceutically acceptable saltform thereof in an amount effective to treat a thromboembolic disorder.

The present invention provides a novel method, comprising: administeringa compound of the present invention or a pharmaceutically acceptablesalt form thereof in an amount effective to treat a thromboembolicdisorder.

The present invention provides novel lactam-containing compounds andderivatives thereof for use in therapy.

The present invention provides the use of novel lactam-containingcompounds for the manufacture of a medicament for the treatment of athromboembolic disorder.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat lactam-containing compounds of Formula I:P₄-P-M-M₄  Iwherein P₄, P, M, and M₄ are defined below, or pharmaceuticallyacceptable salt or prodrug forms thereof, are effective factor Xainhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In an embodiment, the present invention provides a novel compound ofFormula I:P₄-P-M-M₄  Ior a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

-   M is a 3–10 membered carbocycle or a 4–10 membered heterocycle,    consisting of: carbon atoms and 1–3 heteroatoms selected from O,    S(O)_(p), N, and NZ²;-   ring M is substituted with 0–3 R^(1a) and 0–2 carbonyl groups, and    there are 0–3 ring double bonds;-   P is fused onto ring M and is a 5, 6, or 7 membered carbocycle or a    5, 6, or 7 membered heterocycle, consisting of: carbon atoms and 1–3    heteroatoms selected from O, S(O)_(p), and N;-   ring P is substituted with 0–3 R^(1a) and 0–2 carbonyl groups, and    there are 0–3 ring double bonds;-   alternatively, ring P is absent and P₄ is directly attached to ring    M, provided that when ring P is absent, P₄ and M₄ are attached to    the 1,2, 1,3, or 1,4 positions of ring M;-   one of P₄ and M₄ is -Z-A-B and the other -G₁-G;-   G is a group of Formula IIa or IIb:-   ring D, including the two atoms of Ring E to which it is attached,    is a 5–6 membered ring consisting of: carbon atoms and 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p);-   ring D is substituted with 0–2 R and there are 0–3 ring double    bonds;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, and is substituted with 1–2 R;-   alternatively, ring D is absent and ring E is selected from phenyl,    pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,    imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl,    and ring E is substituted with 1–2 R;-   alternatively, ring D is absent and ring E is selected from phenyl,    pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,    imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl,    and ring E is substituted with 1 R and with a 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), wherein the 5–6    membered heterocycle is substituted with 0–1 carbonyl and 1–2 R and    there are 0–3 ring double bonds;-   R is selected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃,    OCH(CH₃)₂, OCH₂CH₂CH₃, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹,    ONHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂,    C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂, CH₂CH₂NH₂,    CH₂CH₂NH(C₁₋₃ alkyl), CH₂CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)C(O)H,    (CR⁸R⁹)_(t)C(O)R^(2c), (CR⁸R⁹)_(t)NR⁷R⁸, (CR⁸R⁹)_(t)C(O)NR⁷R⁸,    (CR⁸R⁹)_(t)NR⁷C(O)R⁷, (CR⁸R⁹)_(t)OR³, (CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸,    (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷, (CR⁸R⁹)_(t)SR³, (CR⁸R⁹)_(t)S(O)R³,    (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃;-   alternatively, when 2 R groups are attached to adjacent atoms, they    combine to form methylenedioxy or ethylenedioxy;-   A is selected from:    -   C₃₋₁₀ carbocycle substituted with 0–2 R⁴, and    -   5–12 membered heterocycle consisting of: carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0–2 R⁴;    -   provided that A is other than a dihydro-benzopyran;-   B is    provided that Z and B are attached to different atoms on A and that    the A-X-N moiety forms other than a N-N-N group;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 4–8 membered monocyclic or bicyclic ring consisting of,    in addition to the N-Q₁ group shown, carbon atoms and 0–2    heteroatoms selected from NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 4–8 membered monocyclic or bicyclic ring    to which another ring is fused, wherein:    -   the 4–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–2 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂ and 0–2 double bonds are present        within the ring;    -   the fusion ring is phenyl or a 5–6 membered heteroaromatic        consisting of carbon atoms and 1–2 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂;    -   ring Q, which includes the 4–7 membered ring and the fusion        ring, is substituted with 0–3 R^(4a);-   alternatively, two non-adjacent atoms of one of the rings of ring Q    are bridged with 1–2 atoms selected from:    -   carbon atoms, NR^(4c), O, S, S(O), and S(O)₂, provided bonds        other than O—O, S(O)_(p)—O, S(O)_(p)—S(O)_(p), N—O, and        N—S(O)_(p) are present;-   X is absent or is selected from —(CR²R^(2a))₁₋₄—,    —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(αNR^(1c))—, —CR²(NR^(1c)R²)—,    —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)—,    —S(O)₂—, —SCR²R^(2a)—, —S(O)CR²R^(2a)—, —S(O)₂CR²R^(2a)—,    —CR²R^(2a)S(O)—, —CR²R^(2a)S(O)₂—, —S(O)₂NR²CR²R^(2a)—, —NR²S(O)₂—,    —CR²R^(2a)NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —NR²C(O)—,    —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)NR²C(O)—,    —NR²CR²R^(2a)—, and —OCR²R^(2a)—;-   G₁ is absent or is selected from (CR³R^(3a))₁₋₅,    (CR³R^(3a))₀₋₂CR³═CR³(CR³R^(3a))₀₋₂,    (CR³R^(3a))₀₋₂C≡C(CR³R^(3a))₀₋₂, (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)OC(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)OC(O)N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)C(O)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)C(O)N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)C(S)N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)N^(3b)S(O)₂N^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3e)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)(CR³R^(3a))_(u)C(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)C(O)(CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(u)C(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)C(O)(CR³R^(3a))_(u)C(O)NR^(3b)(CR³R^(3a)) ,    (CR³R^(3a))_(u)S(O)NR^(3b)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)NR^(3b)S(O)₂(CR³R^(3a))_(w), and    (CR³R^(3a))_(u)S(O)₂NR^(3b)C(O)NR^(3b)CR³R^(3a))_(w), wherein u+w    total 0, 1, 2, 3, or 4, provided that G₁ does not form an N—S,    NCH₂N, NCH₂O, or NCH₂S bond with either group to which it is    attached;-   Z is selected from a bond, —(CR³R^(3e))₁₋₄—,    (CR³R^(3e))_(q)O(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)C(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)C(O)O(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)OC(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)C(O)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)C(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)OC(O)O(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)OC(O)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)C(O)O(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)C(O)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)C(O)(CR³R^(3e))_(q)C(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)(CR³R^(3e))_(q)C(O)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)C(O)(CR³R^(3e))_(q)C(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)C(O)(CR³R^(3e))_(q)C(O)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)C(O)(CR³R^(3e))_(q)C(O)NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)S(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)S(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)S(O)₂(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)SO₂NR^(3b)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)NR^(3b)SO₂(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)S(O)NR^(3b)C(O)(CR³R^(3e))_(q1),    (CR³R^(3e))_(q)C(O)NR^(3b)S(O)₂(CR³R^(3e))_(q1), and    (CR³R^(3e))_(q)NR^(3b)SO₂NR^(3b)(CR³R^(3e))_(q1), wherein q+q1 total    0, 1, 2, 3, or 4, provided that Z does not form a N—S, NCH₂N, NCH₂O,    or NCH₂S bond with either group to which it is attached;-   provided that B-A-Z form other than a pyridone-phenyl-CH₂,    pyridone-pyridyl-CH₂, or pyridone-pyrimidyl-CH₂, wherein the    pyridone, phenyl, pyridyl, and pyrimidyl groups are substituted or    unsubstituted;-   Z² is selected from H, S(O)₂NHR^(3b), C(O)R^(3b), C(O)NHR^(3b),    C(O)OR^(3f), S(O)R^(3f), S(O)₂R^(3f), C₁₋₆ alkyl substituted with    0–2 R^(1a), C₂₋₆ alkenyl substituted with 0–2 R^(1a), C₂₋₆ alkynyl    substituted with 0–2 R^(1a), —(C₀₋₄ alkyl)-C₃₋₁₀ carbocycle    substituted with 0–3 R^(1a), and —(C₀₋₄ alkyl)-5–10 membered    heterocycle substituted with 0–3 R^(1a) and consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p);-   R^(1a), at each occurrence, is selected from H,    —(CR³R^(3a))_(r)—R^(1b), —(CR³R^(3a))_(r)—CR³R^(1b)R^(1b),    —(CR³R^(3a))_(r)—O—(CR³R^(3a))_(r)—R^(1b), —C₂₋₆ alkenylene-R^(1b),    —C₂₋₆ alkynylene-R^(1b), —(CR³R^(3a))_(r)—C(═NR^(1b))NR³R^(1b),    NR³CR³R^(3a)R^(1c), OCR³R^(3a)R^(1c), SCR³R^(3a)R^(1c),    NR³(CR³R^(3a))₂ (CR³R^(3a))_(t)R^(1b),    C(O)NR²(CR³R^(3a))₂(CR³R^(3a))_(t)R^(1b),    CO₂(CR³R^(3a))₂(CR³R^(3a))_(t)R^(1b),    O(CR³R^(3a))₂(CR³R^(3a))_(t)R^(1b),    S(CR³R^(3a))₂(CR³R^(3a))_(t)R^(1b), S(O)_(p)(CR³R^(3a))_(r)R^(1d),    O(CR³R^(3a))_(r)R^(1d), NR³(CR³R^(3a))_(r)R^(1d),    OC(O)NR³(CR³R^(3a))_(r)R^(1d), NR³C(O)NR³(CR³R^(3a))_(r)R^(1d),    NR³C(O)O(CR³R^(3a))_(r)R^(1d), and NR³C(O)(CR³R^(3a))_(r)R^(1d),    provided that R^(1a) forms other than an N-halo, N—S, O—O, or N—CN    bond;-   alternatively, when two R^(1a) groups are attached to adjacent    atoms, together with the atoms to which they are attached they form    a 5–7 membered ring consisting of: carbon atoms and 0–2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), this ring    being substituted with 0–2 R^(4b) and 0–3 ring double bonds;-   R^(1b) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —NO₂,    —CHO, (CF₂)_(r)CF₃, (CR³R^(3a))_(r)OR², NR²R^(2a), C(O)R^(2b),    CO₂R^(2b), OC(O)R², (CF₂)_(r)CO₂R^(2a), S(O)_(p)R^(2b),    NR₂(CH₂)_(r)OR², C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR²,    NR²C(O)₂R^(2a), OC(O)NR²R^(2a), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR²,    SO₂NR²R^(2a), NR²SO₂R², C(O)NR²SO₂R², C₃₋₆ carbocycle substituted    with 0–2 R^(4b), and 5–10 membered heterocycle consisting of carbon    atoms and from 1–4 heteroatoms selected from the group consisting of    N, O, and S(O)_(p), and substituted with 0–2 R^(4b), provided that    R^(1b) forms other than an 0–0, N-halo, N—S, or N—CN bond;-   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R², S(O)₂R², and SO₂NR²R^(2a);-   R^(1d) is selected from C₃₋₆ carbocycle substituted with 0–2 R^(4b)    and 5–10 membered heterocycle consisting of carbon atoms and from    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b), provided that R^(1d)    forms other than an N—S bond;-   R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,    —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0–2 R^(4b), and    —(CH₂)_(r)-5–10 membered heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl,    benzyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0–2 R^(4b), and    —(CH₂)_(r)-5–10 membered heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–2 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy    substituted with 0–2 R^(4b), C₁₋₆ alkyl substituted with 0–2 R^(4b),    —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0–2 R^(4b), and    —(CH₂)_(r)-5–10 membered heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0–2 R^(4b),    and —(CH₂)_(r)-5–10 membered heterocycle containing from 1–4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,

CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, and phenyl;

-   R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, benzyl, and phenyl;-   alternatively, R³ and R^(3a), together with the nitrogen atom to    which they are attached, combine to form a 5 or 6 membered    saturated, partially unsaturated, or unsaturated ring consisting of:    carbon atoms, the nitrogen atom to which R³ and R^(3a) are attached,    and 0–1 additional heteroatoms selected from the group consisting of    N, O, and S(O)_(p);-   R^(3b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0–2 R^(1a), C₂₋₆ alkenyl substituted with 0–2    R^(1a), C₂₋₆ alkynyl substituted with 0–2 R^(1a), —(C₀₋₄ alkyl)-5–10    membered carbocycle substituted with 0–3 R^(1a), and —(C₀₋₄    alkyl)-5–10 membered heterocycle substituted with 0–3 R^(1a) and    consisting of: carbon atoms and 1–4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p);    -   R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃,        CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,        C(CH₃)₃, benzyl, and phenyl;    -   R^(3d), at each occurrence, is selected from H, CH₃, CH₂CH₃,        CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,        C₁₋₄ alkyl-phenyl, and C(═O)R^(3c);-   R^(3e), at each occurrence, is selected from H, SO₂NHR³, SO₂NR³R³,    C(O)R³, C(O)NHR³, C(O)OR^(3f), S(O)R^(3f), S(O)₂R^(3f), C₁₋₆ alkyl    substituted with 0–2 R^(1a), C₂₋₆ alkenyl substituted with 0–2    R^(1a), C₂₋₆ alkynyl substituted with 0–2 R^(1a), —(C₀₋₄ alkyl)-5–10    membered carbocycle substituted with 0–3 R^(1a), and —(C₀₋₄    alkyl)-5–10 membered heterocycle substituted with 0–3 R^(1a) and    consisting of: carbon atoms and 1–4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p);-   R^(3f), at each occurrence, is selected from: C₁₋₆ alkyl substituted    with 0–2 R^(1a), C₂₋₆ alkenyl substituted with 0–2 R^(1a), C₂₋₆    alkynyl substituted with 0–2 R^(1a), —(C₀₋₄ alkyl)-5–10 membered    carbocycle substituted with 0–3 R^(1a), and —(C₀₋₄ alkyl)-5–10    membered heterocycle substituted with 0–3 R^(1a) and consisting of:    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p);-   R⁴, at each occurrence, is selected from H, ═O, (CR³R^(3a))_(r)OR²,    F, Cl, Br, I, C₁₋₄ alkyl, (CR³R^(3a))_(r)CN, (CR³R^(3a))_(r)NO₂,    (CR³R^(3a))_(r)NR²R^(2a), (CR³R^(3a))_(r)C(O)R^(2c),    (CR³R^(3a))_(r)NR²C(O)R^(2b), (CR³R^(3a))_(r)C(O)NR²R^(2a),    (CR³R^(3a))_(r)NR²C(O)NR²R^(2a), (CR³R^(3a))_(r)C(═NR²)NR²R^(2a),    (CR³R^(3a))_(r)C(═NS(O)₂R⁵)NR²R^(2a),    (CR³R^(3a))_(r)NHC(═NR²)NR²R^(2a),    (CR³R^(3a))_(r)C(O)NHC(═NR²)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),    (CR³R^(3a))_(r)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO₂—C₁₋₄ alkyl,    (CR³R^(3a))_(r)NR²SO₂R⁵, (CR³R^(3a))_(r)S(O)_(p)R^(5a),    (CR³R^(3a))_(r)(CH₂)_(r)CF₃, NHCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c),    NH(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b),    S(CH₂)₂(CH₂)_(t)R^(1b), (CR³R^(3a))_(r)-5–6 membered carbocycle    substituted with 0–1 R⁵, and a (CR³R^(3a))_(r)-5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–1 R⁵;-   R^(4a), at each occurrence, is selected from H, ═O,    (CR³R^(3a))_(r)OR², (CR³R^(3a))_(r)F, (CR³R^(3a))_(r)Br,    (CR³R^(3a))_(r)Cl, C₁₋₄ alkyl, (CR³R^(3a))_(r)CN,    (CR³R^(3a))_(r)NO₂, (CR³R^(3a))_(r)NR²R^(2a),    (CR³R^(3a))_(r)C(O)R^(2c), (CR³R^(3a))_(r)NR²C(O)R^(2b),    (CR³R^(3a))_(r)C(O)NR²R^(2a), (CR³R^(3a))_(r)N═CHOR³,    (CR³R^(3a))_(r)C(O)NH(CH₂)₂NR²R^(2a),    (CR³R^(3a))_(r)NR²C(O)NR²R^(2a), (CR³R^(3a))_(r)C(═NR²)NR²R^(2a),    (CR³R^(3a))_(r)NHC(═NR²)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),    (CR³R^(3a))_(r)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO₂—C₁₋₄ alkyl,    (CR³R^(3a))_(r)C(O)NHSO₂—C₁₋₄ alkyl, (CR³R^(3a))NR²SO₂R⁵,    (CR³R^(3a))_(r)S(O)_(p)R^(5a), (CR³R^(3a))_(r)(CF₂)_(r)CF₃,    (CR³R^(3a))_(r)-5–6 membered carbocycle substituted with 0–1 R⁵, and    a (CR³R^(3a))_(r)-5–6 membered heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–1 R⁵;-   R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³,    (CH₂)_(r)F, (CH₂)_(r)Cl, (CH₂)_(r)Br, (CH₂)_(r)I, C₁₋₄ alkyl,    (CH₂)_(r)CN, (CH₂)_(r)NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,    (CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a),    (CH₂)_(r)—C(O)NR³R^(3a), (CH₂)_(r)NR³C(O)NR³R^(3a),    (CH₂)_(r)—C(═NR³)NR³R^(3a), (CH₂)_(r)NR³C(═NR³)NR³R^(3a),    (CH₂)_(r)SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂NR³R^(3a),    (CH₂)_(r)NR³SO₂—C₁₋₄ alkyl, (CH₂)_(r)NR³SO₂CF₃,    (CH₂)_(r)NR³SO₂-phenyl, (CH₂)_(r)S(O)_(p)CF₃, (CH₂)_(r)S(O)_(p)—C₁₋₄    alkyl, (CH₂)_(r)S(O)_(p)-phenyl, and (CH₂)_(r)(CF₂)_(r)CF₃;-   R^(4c), at each occurrence, is selected from H, C₁₋₄ alkyl    (CR³R^(3a))_(r1)OR², (CR³R^(3a))_(r1)F, (CR³R^(3a))_(r1)Br,    (CR³R^(3a))_(r1)Cl, (CR³R^(3a))_(r1)CN, (CR³R^(3a))_(r1)NO₂,    (CR³R^(3a))_(r1)NR²R^(2a), (CR³R^(3a))_(r)C(O)R^(2c),    (CR³R^(3a))_(r1)NR²C(O)R^(2b), (CR³R^(3a))_(r)C(O) NR²R^(2a),    (CR³R^(3a))_(r1)N═CHOR³, (CR³R^(3a))_(r)C(O)NH(CH₂)₂NR²R^(2a),    (CR³R^(3a))_(r1)NR²C(O)NR²R^(2a), (CR³R^(3a))_(r1)C(═NR²)NR²R^(2a),    (CR³R^(3a))_(r1)NHC(═NR²)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),    (CR³R^(3a))_(r1)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r1)NR²SO₂—C₁₋₄ alkyl,    (CR³R^(3a))_(r)C(O)NHSO₂—C₁₋₄ alkyl, (CR³R^(3a))_(r1)NR²SO₂R⁵,    (CR³R^(3a))_(r)S(O)_(p)R^(5a), (CR³R^(3a))_(r)(CF₂)_(r)CF₃,    (CR³R^(3a))_(r)-5–6 membered carbocycle substituted with 0–1 R⁵, and    a (CR³R^(3a))_(r)-5–6 membered heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, C₁₋₆ alkyl, ═O,    (CH₂)_(r)OR³, F, Cl, Br, I, —CN, NO₂, (CH₂)_(r)NR³R^(3a),    (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a),    (CH₂)_(r)C(O)NR³R^(3a), (CH₂)_(r)NR³C(O)NR³R^(3a),    (CH₂)_(r)CH(═NOR^(3d)), (CH₂)_(r)C(═NR³)NR³R^(3a),    (CH₂)_(r)NR³C(═NR³)NR³R^(3a), (CH₂)_(r)SO₂NR³R^(3a),    (CH₂)_(r)NR³SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂—C₁₋₄ alkyl,    (CH₂)_(r)NR³SO₂CF₃, (CH₂)_(r)NR³SO₂-phenyl, (CH₂)_(r)S(O)_(p)CF₃,    (CH₂)_(r)S(O)_(p)—C₁₋₄ alkyl, (CH₂)_(r)S(O)_(p)-phenyl,    (CF₂)_(r)CF₃, phenyl substituted with 0–2 R⁶, naphthyl substituted    with 0–2 R⁶, and benzyl substituted with 0–2 R⁶;-   R^(5a), at each occurrence, is selected from C₁₋₆ alkyl,    (CH₂)_(r)OR³, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,    (CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a),    (CH₂)_(r)C(O)NR³R^(3a), (CF₂)_(r)CF₃, phenyl substituted with 0–2    R⁶, naphthyl substituted with 0–2 R⁶, and benzyl substituted with    0–2 R⁶, provided that R^(5a) does not form a S—N or S(O)_(p)—C(O)    bond;-   R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo,    C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),    NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂,    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl;-   R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)—, C₁₋₆ alkyl-O—, (CH₂)_(n)-phenyl, C₁₋₄ alkyl-OC(O)—,    C₆₋₁₀ aryl-O—, C₆₋₁₀ aryl-OC(O)—, C₆₋₁₀ aryl-CH₂—C(O)—, C₁₋₄    alkyl-C(O)O—C₁₋₄ alkyl-OC(O)—, C₆₋₁₀ aryl-C(O)O—C₁₋₄ alkyl-OC(O)—,    C₁₋₆ alkyl-NH₂—C(O)—, phenyl-NH₂—C(O)—, and phenyl-C₁₋₄ alkyl-C(O)—;-   R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl, and    (CH₂)_(n)-phenyl;-   alternatively, R⁷ and R⁸, when attached to the same nitrogen,    combine to form a 5–10 membered heterocyclic ring consisting of    carbon atoms and 0–2 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl, and    (CH₂)_(n)-phenyl;-   n, at each occurrence, is selected from 0, 1, 2, and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;-   r1, at each occurrence, is selected from 1, 2, 3, 4, 5, and 6;-   t, at each occurrence, is selected from 0, 1, 2, and 3; and,-   provided that when:    -   (a) ring M is phenyl and is substituted 1,2 by M₄ and P₄ and G₁        is present, then Z-A is other than NHC(O)-thienyl,        NHCH₂-thienyl, NHC(O)-benzothienyl, and NHCH₂-benzothienyl; and,    -   (b) B is 2-oxo-1-pyrrolidinyl and rings P-M are        1,7-dihydro-2-methyl-6H-purin-6-one, then G-G₁ is other then        unsubstituted phenyl.

In a preferred embodiment, the present invention provides a novelcompound of Formula II:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

-   ring M, including P₁, P₂, M₁, and M₂, is a 5, 6, or 7 membered    carbocycle or a 5, 6, or 7 membered heterocycle, consisting of:    carbon atoms and 1–3 heteroatoms selected from O, S(O)_(p), N, and    NZ²;-   ring M is substituted with 0–2 R^(1a) and 0–2 carbonyl groups, and    there are 0–3 ring double bonds;-   ring P, including P₁, P₂, and P₃, is a 5 or 6 membered aromatic    heterocycle, consisting of: carbon atoms and 1–3 heteroatoms    selected from O, S(O)_(p), and N;-   alternatively, ring P, including P₁, P₂, and P₃, is a 5 or 6    membered dihydro-aromatic heterocycle, consisting of: carbon atoms    and 1–3 heteroatoms selected from O, S(O)_(p), and N;-   ring P is substituted with 0–2 R^(1a);-   one of P₄ and M₄ is -Z-A-B and the other -G₁-G;-   G is a group of Formula IIa or IIb:-   ring D, including the two atoms of Ring E to which it is attached,    is a 5–6 membered ring consisting of: carbon atoms and 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p);-   ring D is substituted with 0–2 R and there are 0–3 ring double    bonds;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, and is substituted with 1–2 R;-   alternatively, ring D is absent, and ring E is selected from phenyl,    pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1–2    R;-   alternatively, ring D is absent, ring E is selected from phenyl,    pyridyl, and thienyl, and ring E is substituted with 1 R and    substituted with a 5 membered heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), wherein the 5 membered heterocycle is substituted    with 0–1 carbonyl and 1–2 R and there are 0–3 ring double bonds;-   R is selected from H, C₁₋₄ alkyl, F, Cl, OH, OCH₃, OCH₂CH₃,    OCH(CH₃)₂, CN, C(═NH)NH₂, C(═NH)NHOH, C(═NH)NHOCH₃, NH₂, NH(C₁₋₃    alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl),    CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)NR⁷R⁸, C(O)NR⁷R⁸, CH₂C(O)NR⁷R⁸,    S(O)_(p)NR⁷R⁸, CH₂S (O)_(p)NR⁷R⁸, SO₂R³, and OCF₃;-   alternatively, when 2 R groups are attached to adjacent atoms, they    combine to form methylenedioxy or ethylenedioxy;-   A is selected from:    -   C₅₋₁₀ carbocycle substituted with 0–2 R⁴, and    -   5–10 membered heterocycle consisting of: carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0–2 R⁴;    -   provided that A is other than a dihydro-benzopyran;-   B is    provided that Z and B are attached to different atoms on A and that    the A-X-N moiety forms other than a N-N-N group;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 4–7 membered monocyclic or tricyclic ring consisting of,    in addition to the N-Q₁ group shown, carbon atoms and 0–2    heteroatoms selected from NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 4–7 membered ring to which another ring    is fused, wherein:    -   the 4–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–2 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂ and 0–1 double bonds are present        within the ring;    -   the fusion ring is phenyl or a 5–6 membered heteroaromatic        consisting of carbon atoms and 1–2 heteroatoms selected from        NR^(4c), O, and S;    -   ring Q, which includes the 4–7 membered ring and the fusion        ring, is substituted with 0–3 R^(4a);-   X is absent or is selected from —(CR²R^(2a))₁₋₄—, —C(O)—,    —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)₂—, —S(O)₂CR²R^(2a)—,    —CR²R^(2a)S(O)₂—, —NR²S(O)₂—, —NR²CR²R^(2a)—, and —OCR²R^(2a)—;-   Z is selected from a bond, CH₂, CH₂CH₂, CH₂O, OCH₂, C(O), NH, CH₂NH,    NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), NHC(O)CH₂C(O)NH, S(O)₂,    CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not    form a N—S, NCH₂N, NCH₂O, or NCH₂S bond with either group to which    it is attached;-   Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R^(3b),    S(O)R^(3f), and S(O)₂R^(3f);-   R^(1a) is selected from H, —(CH₂)_(r)—R^(1b), —(CH(CH₃))_(r)—R^(1b),    —(C(CH₃)₂)_(r)—R^(1b), NHCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c),    NH(CH₂)₂(CH₂)_(t)R^(1b), and O(CH₂)₂(CH₂)_(t)R^(1b), provided that    R^(1a) forms other than an N-halo, N—S, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to adjacent    atoms, together with the atoms to which they are attached they form    a 5–7 membered ring consisting of: carbon atoms and 0–2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), this ring    being substituted with 0–2 R^(4b) and 0–3 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, F, Cl,    Br, I, —CN, —CHO, CF₃, OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b),    OC(O)R², CO₂R^(2a), S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b),    NR²C(O)NHR², NR²C(O)₂R^(2a), OC(O)NR²R^(2a), C(O)NR²R^(2a),    C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R², C₅₋₆ carbocycle    substituted with 0–2 R^(4b), and 5–6 membered heterocycle consisting    of carbon atoms and from 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–2 R^(4b),    provided that R^(1b) forms other than an O—O, N-halo, N—S, or N—CN    bond;-   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R², S(O)₂R², and SO₂NR²R^(2a);-   R², at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2 R^(4b), a C₅₋₆    carbocyclic-CH₂-group substituted with 0–2 R^(4b), and 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2 R^(4b), and    5–6 membered heterocycle consisting of: carbon atoms and 1–4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–2 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2    R^(4b), and 5–6 membered heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2    R^(4b), and 5–6 membered heterocycle containing from 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(4b);-   R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, benzyl, and phenyl;-   R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, and phenyl;-   alternatively, R³ and R^(3a), together with the nitrogen atom to    which they are attached, combine to form a 5 or 6 membered    saturated, partially unsaturated, or unsaturated ring consisting of:    carbon atoms and the nitrogen atom to which R³ and R^(3a) are    attached;-   R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, benzyl, and phenyl;-   R^(3d), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, CH₂CH₂-phenyl, and C(═O)R^(3c);-   R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR²,    (CH₂)₂OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R^(5a), CF₃, CF₂CF₃, 5–6    membered carbocycle substituted with 0–1 R⁵, and a 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–1 R⁵;-   R^(4a), at each occurrence, is selected from H, ═O, CH₂OR², OR²,    CH₂F, F, CH₂Br, Br, CH₂Cl, Cl, C₁₋₄ alkyl, CH₂—CN, —CN, CH₂NO₂, NO₂,    CH₂NR²R^(2a), NR²R^(2a), CH₂—C(O)R^(2c), C(O)R^(2c), NR²C(O)R^(2b),    (CH₂)_(r)C(O)NR²R^(2a), NR²C(O)NR²R^(2a), (CH₂)_(r)SO₂NR²R^(2a),    NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵,    (CH₂)_(r)S(O)_(p)R^(5a), CH₂CF₃, CF₃, CH₂-5–6 membered carbocycle    substituted with 0–1 R⁵, 5–6 membered carbocycle substituted with    0–1 R⁵, and a CH₂-5–6 membered heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–1 R⁵, and 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–1 R⁵;-   R^(4b), at each occurrence, is selected from H, ═O, OR³ CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a), C(O)R³,    CH₂—C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a),    CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂C(O)NR³R^(3a), NR³C(O)NR³R^(3a),    CH₂NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), CH₂C(═NR³)NR³R^(3a),    NR³C(═NR³)NR³R^(3a), CH₂NR³C(═NR₃)NR³R^(3a), SO₂NR³R^(3a),    CH₂SO₂NR³R^(3a), NR³SO₂NR³R^(3a), CH₂NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄    alkyl, CH₂NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, CH₂NR³SO₂CF₃, NR³SO₂-phenyl,    CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, CH₂S(O)_(p)-phenyl, CF₃,    and CH₂—CF₃;-   R^(4c), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, CH₂OR², CH₂F, CH₂Br, CH₂Cl CH₂CN, CH₂NO₂, CH₂NR²R^(2a),    C(O)R^(2c), CH₂C(O)R^(2c), CH₂NR²C(O)R^(2b), C(O)NR²R^(2a),    CH₂C(O)NR²R^(2a), CH₂NR²C(O)NR²R^(2a), SO₂NR²R^(2a),    CH₂SO₂NR²R^(2a), CH₂NR²SO₂NR²R^(2a), CH₂NR²SO₂—C₁₋₄ alkyl,    C(O)NHSO₂—C₁₋₄ alkyl, CH₂C(O)NHSO₂—C₁₋₄ alkyl, CH₂NR²SO₂R⁵,    S(O)_(p)R^(5a), CH₂S(O)_(p)R^(5a), CF₃, CH₂CF₃, 5–6 membered    carbocycle substituted with 0–1 R⁵, CH₂-5–6 membered carbocycle    substituted with 0–1 R⁵, 5–6 membered heterocycle consisting of:    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and substituted with 0–1 R⁵, and a CH₂-5–6    membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a),    C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a),    C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═OR^(3d)), C(═NR³)NR³R^(3a),    NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄    alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0–2 R⁶, naphthyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; and,    -   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,        CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,        CH(CH₃)CH₂CH₃, C(CH₃)₃, CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),        C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a),        C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and        NR²SO₂C₁₋₄ alkyl.

In another preferred embodiment, the present invention provides a novelcompound, wherein:

-   ring M is substituted with 0–2 R^(1a) and is selected from the    group:-   ring P, including P₁, P₂, P₃, and P₄ is selected from group:-   one of P₄ and M₄ is -Z-A-B and the other -G₁-G;-   G is selected from the group:-   G₁ is absent or is selected from (CR³R^(3a))₁₋₃,    (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)C(O)(CR³R^(3a))_(u)C(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)S(O)₂(CR³R^(3a))_(w), and    (CR³R^(3a))_(u)S(O)₂NR^(3b)(CR³R^(3a))_(w), wherein u+w total 0, 1,    or 2, provided that G₁ does not form a N—S, NCH₂N, NCH₂O, or NCH₂S    bond with either group to which it is attached;-   A is selected from one of the following carbocyclic and heterocyclic    groups which are substituted with 0–2 R⁴;    -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,        morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,        1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,        1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,        1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,        benzothiofuranyl, indolinyl, indolyl, benzimidazolyl,        benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl,        benzisothiazolyl, and isoindazolyl;-   B is    provided that Z and B are attached to different atoms on A;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 5–7 membered ring consisting of, in addition to the N-Q₁    group shown, carbon atoms and 0–2 heteroatoms selected from NR^(4c),    O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 5–7 membered ring to which another ring    is fused, wherein:    -   the 5–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–2 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂, and 0–1 double bonds are present        within the ring;    -   the fusion ring is phenyl or a 5–6 membered heteroaromatic        consisting of carbon atoms and 1–2 heteroatoms selected from        NR^(4c), O, and S;    -   ring Q, which includes the 5–7 membered ring and the fusion        ring, is substituted with 0–3 R^(4a);-   R^(1a) is selected from H, R^(1b), CH(CH₃)R^(1b), C(CH₃)₂R^(1b),    CH₂R^(1b), and CH₂CH₂R^(1b), provided that R^(1a) forms other than    an N-halo, N—S, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to adjacent    atoms, together with the atoms to which they are attached they form    a 5–6 membered ring consisting of: carbon atoms and 0–2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), this ring    being substituted with 0–2 R^(4b) and 0–3 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, F, Cl, Br, —CN, —CHO, CF₃,    OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b), OC(O)R², CO₂R^(2a),    S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b), C(O)NR²R^(2a),    SO₂NR²R^(2a), NR²SO₂R², phenyl substituted with 0–2 R^(4b), and 5–6    membered aromatic heterocycle consisting of carbon atoms and from    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b), provided that R^(1b)    forms other than an O—O, N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, phenyl substituted with 0–2 R^(4b), a benzyl    substituted with 0–2 R^(4b), and a 5–6 membered aromatic heterocycle    consisting of: carbon atoms and 1–4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p), and substituted with 0–2    R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0–2 R^(4b), and    5–6 membered aromatic heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–2 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0–2    R^(4b), and 5–6 membered aromatic heterocycle consisting of carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0–2 R^(4b), and 5–6 membered aromatic    heterocycle containing from 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–2 R^(4b);-   R⁴, at each occurrence, is selected from H, CH₂OR², (CH₂)₂OR², OR²,    F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), SO₂NR²R^(2a), CF₃, and CF₂CF₃;-   R^(4a), at each occurrence, is selected from H, ═O, CH₂OR², OR², F,    Br, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, CH₂NR²R^(2a), NR²R^(2a),    C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),    SO₂NR²R^(2a), and —CF₃;-   R^(4b), at each occurrence, is selected from H, ═O, OR³CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, CH₂—C(O)R³, C(O)OR^(3c), CH₂—C(O)OR^(3c),    NR³C(O)R^(3a), CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂—C(O)NR³R^(3a),    SO₂NR³R^(3a), CH₂SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, CH₂NR³SO₂—C₁₋₄    alkyl, NR³SO₂-phenyl, CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃,    S(O)_(p)—C₁₋₄ alkyl, CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,    CH₂S(O)_(p)-phenyl, and CF₃;-   R^(4c), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, CH₂OR², CH₂F, CH₂Br, CH₂Cl, CH₂CN, CH₂NO₂, CH₂NR²R^(2a),    C(O)R^(2c), CH₂C(O)R^(2c), CH₂NR²C(O)R^(2b), C(O)NR²R^(2a),    CH₂C(O)NR²R^(2a), SO₂NR²R^(2a), CH₂SO₂NR²R^(2a), S(O)_(p)R^(5a),    CH₂S(O)_(p)R^(5a), CF₃, phenyl substituted with 0–1 R⁵, and benzyl    substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,    NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0–2 R⁶, naphthyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), SO₂NR²R^(2a), and    NR²SO₂C₁₋₄ alkyl.

In another preferred embodiment, the present invention provides a novelcompound, wherein:

-   ring M is substituted with 0–2 R^(1a) and is selected from the    group:-   ring P, including P₁, P₂, P₃, and P₄ is selected from group:-   one of P₄ and M₄ is -A-B and the other -G;-   G is selected from the group:-   G₁ is absent or is selected from CH₂, CH₂CH₂, CH₂O, OCH₂, NH, CH₂NH,    NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),    SO₂NH, and NHSO₂, provided that G₁ does not form a N—S, NCH₂N,    NCH₂O, or NCH₂S bond with either group to which it is attached;-   A is selected from phenyl, pyridyl, and pyrimidyl, and is    substituted with 0–2 R⁴;-   B is    provided that Z and B are attached to different atoms on A;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 6–7 membered ring consisting of, in addition to the N-Q₁    group shown, carbon atoms and 0–1 heteroatoms selected from NR^(4c),    O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 5–7 membered ring to which another ring    is fused, wherein:    -   the 5–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–1 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂, and 0–1 double bonds are present        within the ring;    -   the fusion ring is phenyl;    -   ring Q, which includes the 5–7 membered ring and the fusion        ring, is substituted with 0–2R^(4a);-   R^(1a) is selected from H, R^(1b), C(CH₃)₂R^(1b), and CH₂R^(1b),    provided that R^(1a) forms other than an N-halo, N—S, or N—CN bond;-   R^(1b) is selected from CH₃, CH₂CH₃, F, Cl, Br, —CN, CF₃, OR²,    NR²R^(2a), C(O)R^(2b), CO₂R^(2b), CO₂R^(2a), S(O)_(p)R²,    C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂R², and 5–6 membered aromatic    heterocycle consisting of carbon atoms and from 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(4b), provided that R^(1b) forms other than    an O—O, N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, phenyl substituted with 0–1 R^(4b), benzyl substituted    with 0–1 R^(4b), and 5–6 membered aromatic heterocycle consisting    of: carbon atoms and 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–1 R^(4b);-   R^(2a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0–1 R^(4b), and    5–6 membered aromatic heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–1 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–1 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0–1 R^(4b), and 5–6 membered aromatic    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–1 R^(4b);-   R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0–1 R^(4b), and 5–6 membered aromatic    heterocycle containing from 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–1 R^(4b);-   R⁴, at each occurrence, is selected from OH, OR², CH₂OR², (CH₂)₂OR²,    F, Br, Cl, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, NR²R^(2a), CH₂NR²R^(2a),    (CH₂)₂NR²R^(2a), CF₃, and CF₂CF₃;-   R^(4a), at each occurrence, is selected from H, ═O, CH₂OR², OR², F,    Br, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, CH₂NR²R^(2a), NR²R^(2a), C(O)R^(2c),    NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, and CF₃;-   R^(4c), at each occurrence, is selected from H, CH₃, CH₂CH₃, phenyl    substituted with 0–1 R⁵, and benzyl substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0–2 R⁶, naphthyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), and SO₂NR²R^(2a).

In another preferred embodiment, the present invention provides a novelcompound, wherein:

-   ring M is substituted with 0–1 R^(1a) and is selected from the    group:-   ring P, including P₁, P₂, P₃, and P₄ is selected from group:-   one of P₄ and M₄ is -A-B and the other -G;-   G is selected from:-   A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,    2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,    2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;-   B is attached to a different atom on A than M and is selected from    the group:-   R^(1a) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂F, CH₂Cl, Br,    CH₂Br, —CN, CH₂CN, CF₃, CH₂CF₃, OCH₃, CH₂OH, C(CH₃)₂OH, CH₂OCH₃,    NH₂, CH₂NH₂, NHCH₃, CH₂NHCH₃, N(CH₃)₂, CH₂N(CH₃)₂, CO₂H, COCH₃,    CO₂CH₃, CH₂CO₂CH₃. SCH₃, CH₂SCH₃, S(O)CH₃, CH₂S(O)CH₃, S(O)₂CH₃,    CH₂S(O)₂CH₃, C(O)NH₂, CH₂C(O)NH₂, SO₂NH₂, CH₂SO₂NH₂, NHSO₂CH₃,    CH₂NHSO₂CH₃, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,    pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N-oxide,    imidazol-1-yl, CH₂-imidazol-1-yl, 4-methyl-oxazol-2-yl,    4-N,N-dimethylaminomethyl-oxazol-2-yl, 1,2,3,4-tetrazol-1-yl,    1,2,3,4-tetrazol-5-yl, CH₂-1,2,3,4-tetrazol-1-yl, and    CH₂-1,2,3,4-tetrazol-5-yl, provided that R^(1a) forms other than an    N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, phenyl substituted with 0–1 R^(4b), benzyl substituted    with 0–1 R^(4b), and 5 membered aromatic heterocycle consisting of:    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and substituted with 0–1 R^(4b);-   R^(2a), at each occurrence, is selected from H, CH₃, and CH₂CH₃;-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–1 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from OCH₃, OCH₂CH₃, CH₃, and    CH₂CH₃;-   R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,    and CH₂CH₃;-   R^(4a), at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, and    C(CH₃)₃;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂-phenyl, S(O)₂CH₃,    S(O)₂-phenyl, and CF₃;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃, OR³,    CH₂OR^(3a), F, Cl, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR³C,    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³    SO₂-phenyl, S(O) ₂—CH₃, S(O)₂-phenyl, CF₃, phenyl substituted with    0–2 R⁶, naphthyl substituted with 0–2 R⁶, and benzyl substituted    with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), CH₂C(O)R^(2b),    NR²C(O)R^(2b), and SO₂NR²R^(2a).

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from:

-   P₄ is -G;-   M₄ is -A-B;-   G is selected from:    and,-   A-B is selected from:

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from:

-   P₄ is -G;-   M₄ is -A-B;-   A-B is selected from:

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from the group:

-   3-methoxy-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7-H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-3-[(methylamino)methyl]-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(3-chloro-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one;-   1-[3-(aminomethyl)-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one;-   1-(3-amino-1,2-benzisoxazol-5-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxohexahydro-1H-azepin-1-yl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperazinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-imidazolidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxotetrahydro-1(2H)-pyrimidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   6-[4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl-4,5,6,7-tetrahydro-1H-pyrazole-[3,4-c]pyridine-3-carboxamide;-   3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)    phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(4-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(4-pyridinyl-N-oxide)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(3-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(3-pyridinyl-N-oxide)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(2-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)    phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-7-oxo-6-[5-(2-oxo-1-piperidinyl)2-pyridinyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(4-methoxyphenyl)-3-(methylsulfonyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-(4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(2-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-[3-(aminomethyl)phenyl]-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   3-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzamide;-   1-(3-chlorophenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(3-chlorophenyl)-7-oxo-6-[4-(2-oxo-1(2H)pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(3-chlorophenyl)-N,N-dimethyl-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(3-chloro-4-fluorophenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile;-   1-(3-amino-1H-indazol-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(3-amino-1,2-benzisoxazol-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(2,3-dihydro-1H-isoindol-5-yl)-6-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-3-(2-pyrrolidin-1-ylmethyl-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   ethyl    1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate;-   1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic    acid;-   1-(4-methoxyphenyl)-N,N-dimethyl-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   N-({1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl}carbonyl)methanesulfonamide;-   1-(4-hydroxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic    acid amide;-   1-(4-methoxyphenyl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(1H-tetraazol-5-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   3-{4-[dimethylamino)methyl]-1,3-oxazol-2-yl}-1-(4-methoxyphenyl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   3-{4-[dimethylamino)methyl]-1,3-oxazol-2-yl}-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperazinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(4-methoxyphenyl)-3-(methylsulfonyl)-6-[4-(2-oxo-1-piperazinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxy-phenyl)-3-(4-methyl-oxazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxy-phenyl)-3-(4-methyl-oxazol-2-yl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   3-acetyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   3-(4,5-dihydro-1H-imidazol-2-yl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxy-phenyl)-3-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxy-phenyl)-3-(1-methyl-1H-imidazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   1-(4-methoxy-phenyl)-3-methyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   3-hydroxymethyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one;-   3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   2-dimethylamino-N-{1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}-N-methylacetamide;-   2-dimethylamino-N-{1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}acetamide;-   N-{1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}-2-pyridin-2-yl-acetamide;-   N-{1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}-2-(1-oxypyridin-2-yl)acetamide;-   6-[4-(1,1-dioxo-116-isothiazolidin-2-yl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic    acid amide;-   N-hydroxy-3-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamidine;-   N-methoxy-3-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamidine;-   1-(3-cyano-4-fluorophenyl-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(3-aminomethyl-4-fluoro-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic    acid amide;-   2-{7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzenesulfonamide;-   2-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzenesulfonamide;-   N-acetyl-2-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzenesulfonamide;-   1-(3-chloro-phenyl)-3-methanesulfonyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   1-(3-chloro-phenyl)-3-methanesulfonyl-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;-   1-(3-chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;    and,-   3-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamide;-   or a pharmaceutically acceptable salt form thereof.

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is of Formula IIIa, IIIb, or IIIc:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

-   ring M, including M₁, M₂, and, if present, M₃, is phenyl or a 3–10    membered carbocyclic or 4–10 membered heterocyclic ring consisting    of: carbon atoms and 1–4 heteroatoms selected from O, S(O)_(p), N,    and NZ²;-   ring M is substituted with 0–3 R^(1a) and 0–2 carbonyl groups, and    there are 0–3 ring double bonds;-   one of P₄ and M₄ is -Z-A-B and the other -G₁-G;-   G is a group of Formula IIa or IIb:-   ring D, including the two atoms of Ring E to which it is attached,    is a 5–6 membered ring consisting of: carbon atoms and 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p);-   ring D is substituted with 0–2 R and there are 0–3 ring double    bonds;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, and is substituted with 1–2 R;-   alternatively, ring D is absent, and ring E is selected from phenyl,    pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1–2    R;-   alternatively, ring D is absent, ring E is selected from phenyl,    pyridyl, and thienyl, and ring E is substituted with 1 R and    substituted with a 5 membered heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), wherein the 5 membered heterocycle is substituted    with 0–1 carbonyl and 1–2 R and there are 0–3 ring double bonds;-   R is selected from H, C₁₋₄ alkyl, F, Cl, OH, OCH₃, OCH₂CH₃,    OCH(CH₃)₂, CN, C(═NH)NH₂, C(═NH)NHOH, C(═NH)NHOCH₃, NH₂, NH(C₁₋₃    alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl),    CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)NR⁷R⁸, C(O)NR⁷R⁸, CH₂C(O)NR⁷R⁸,    S(O)_(p)NR⁷R⁸, CH₂S(O)_(p)NR⁷R⁸, SO₂R³, and OCF₃;-   alternatively, when 2 R groups are attached to adjacent atoms, they    combine to form methylenedioxy or ethylenedioxy;-   A is selected from:    -   C₅₋₁₀ carbocycle substituted with 0–2 R⁴, and    -   5–10 membered heterocycle consisting of: carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0–2 R⁴;    -   provided that A is other than a dihydro-benzopyran;    -   B is        provided that Z and B are attached to different atoms on A and        that the A-X-N moiety forms other than a N-N-N group;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 4–7 membered monocyclic or tricyclic ring consisting of,    in addition to the N-Q₁ group shown, carbon atoms and 0–2    heteroatoms selected from NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 4–7 membered ring to which another ring    is fused, wherein:    -   the 4–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–2 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂ and 0–1 double bonds are present        within the ring;    -   the fusion ring is phenyl or a 5–6 membered heteroaromatic        consisting of carbon atoms and 1–2 heteroatoms selected from        NR^(4c), O, and S;    -   ring Q, which includes the 4–7 membered ring and the fusion        ring, is substituted with 0–3 R^(4a);    -   X is absent or is selected from —(CR²R^(2a))₁₋₄—, —C(O)—,        —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)₂—, —S(O)₂CR²R^(2a)—,        —CR²R^(2a)S(O)₂—, —NR²S(O)₂—, —NR²CR²R^(2a)—, and —OCR²R^(2a)—;-   Z is selected from a bond, CH₂, CH₂CH₂, CH₂O, OCH₂, C(O), NH, CH₂NH,    NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), NHC(O)NH, NHC(O)CH₂C(O)NH,    C(O)NHS(O)₂, S(O)₂, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided    that Z does not form a N—S, NCH₂N, NCH₂O, or NCH₂S bond with either    group to which it is attached;-   Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R^(3b),    S(O)R^(3f), and S(O)₂R^(3f);-   R^(1a) is selected from H, —(CH₂)_(r)—R^(1b), —(CH(CH₃))_(r)—R^(1b),    —(C(CH₃)₂)_(r)—R^(1b), NHCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c),    NH(CH₂)₂(CH₂)_(t)R^(1b), and O(CH₂)₂(CH₂)_(t)R^(1b), provided that    R^(1a) forms other than an N-halo, N—S, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to adjacent    atoms, together with the atoms to which they are attached they form    a 5–7 membered ring consisting of: carbon atoms and 0–2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), this ring    being substituted with 0–2 R^(4b) and 0–3 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, F, Cl,    Br, I, —CN, —CHO, CF₃, OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b),    OC(O)R², CO₂R^(2a), S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b),    NR²C(O)NHR², NR²C(O)₂R^(2a), OC(O)NR²R^(2a), C(O)NR²R^(2a),    C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R², C₅₋₆ carbocycle    substituted with 0–2 R^(4b), and 5–6 membered heterocycle consisting    of carbon atoms and from 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–2 R^(4b),    provided that R^(1b) forms other than an 0–0, N-halo, N—S, or N—CN    bond;-   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R², S(O)₂R², and SO₂NR²R^(2a);-   R², at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2 R^(4b), a C₅₋₆    carbocyclic-CH₂-group substituted with 0–2 R^(4b), and 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2 R^(4b), and    5–6 membered heterocycle consisting of: carbon atoms and 1–4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–2 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2    R^(4b), and 5–6 membered heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0–2    R^(4b), and 5–6 membered heterocycle containing from 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(4b);-   R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, benzyl, and phenyl;-   R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, and phenyl;-   alternatively, R³ and R^(3a), together with the nitrogen atom to    which they are attached, combine to form a 5 or 6 membered    saturated, partially unsaturated, or unsaturated ring consisting of:    carbon atoms and the nitrogen atom to which R³ and R^(3a) are    attached;-   R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, benzyl, and phenyl;-   R^(3d), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, CH₂CH₂-phenyl, and C(═O) R^(3c);-   R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR²,    (CH₂)₂OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R^(5a), CF₃, CF₂CF₃, 5–6    membered carbocycle substituted with 0–1 R⁵, and a 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–1 R⁵;-   R^(4a), at each occurrence, is selected from H, ═O, CH₂OR², OR²,    CH₂F, F, CH₂Br, Br, CH₂Cl, Cl, C₁₋₄ alkyl, CH₂—CN, —CN, CH₂NO₂, NO₂,    CH₂NR²R^(2a), NR²R^(2a), CH₂—C(O)R^(2c), C(O)R^(2c), NR₂C(O)R^(2b),    (CH₂)_(r)C(O)NR²R^(2a), NR²C(O)NR²R^(2a), (CH₂)_(r)SO₂NR²R^(2a),    NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵,    (CH₂)_(r)S(O)_(p)R^(5a), CH₂CF₃, CF₃, CH₂-5–6 membered carbocycle    substituted with 0–1 R⁵, 5–6 membered carbocycle substituted with    0–1 R⁵, and a CH₂-5–6 membered heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–1 R⁵, and 5–6 membered    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–1 R⁵;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a), C(O)R³,    CH₂—C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a),    CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂C(O)NR³R^(3a), NR³C(O)NR³R^(3a),    CH₂NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), CH₂C(═NR³)NR³R^(3a),    NR³C(═NR³)NR³R^(3a), CH₂NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a),    CH₂SO₂NR³R^(3a), NR³SO₂NR³R^(3a), CH₂NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄    alkyl, CH₂NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, CH₂NR³SO₂CF₃, NR³SO₂-phenyl,    CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, CH₂S(O)_(p)-phenyl, CF₃,    and CH₂—CF₃;-   R^(4c), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, CH₂OR², CH₂F, CH₂Br, CH₂Cl, CH₂CN, CH₂NO₂, CH₂NR²R^(2a),    C(O)R^(2c), CH₂C(O)R^(2c), CH₂NR²C(O)R^(2b), C(O)NR²R^(2a),    CH₂C(O)NR²R^(2a), CH₂NR²C(O)NR²R^(2a), SO₂NR²R^(2a), CH₂    SO₂NR²R^(2a), CH₂NR²SO₂NR²R^(2a), CH₂NR²SO₂—C₁₋₄ alkyl,    C(O)NHSO₂—C₁₋₄ alkyl, CH₂C(O)NHSO₂—C₁₋₄ alkyl, CH₂NR²SO₂R⁵,    S(O)_(p)R^(5a), CH₂S(O)_(p)R^(5a), CF₃, CH₂CF₃, 5–6 membered    carbocycle substituted with 0–1 R⁵, CH₂5–6 membered carbocycle    substituted with 0–1 R⁵, 5–6 membered heterocycle consisting of:    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and substituted with 0–1 R⁵, and a CH₂5–6    membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a),    C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a),    C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NOR^(3d)), C(═NR³)NR³R^(3a),    NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄    alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0–2 R⁶, naphthyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH (CH₃)    CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b),    CH₂C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂,    NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl.

In another preferred embodiment, the present invention provides a novelcompound, wherein:

-   ring M, including M₁, M₂, and, if present, M₃, is selected from    phenyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole,    oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,2,4-triazole,    1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,    1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,    1,3,4-thiadiazole, 1,2,3,4-tetrazole, 1,2,3,5-tetrazole, pyran,    thiopyran, thiopyran=1,1-dioxide, pyridine, pyrimidine, pyridazine,    pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,3,4-tetrazine,    dihydro-pyrrole, dihydro-furan, dihydro-thiophene, dihydro-pyrazole,    dihydro-imidazole, dihydro-isoxazole, dihydro-oxazole,    dihydro-isothiazole, dihydro-thiazole, dihydro-1,2,3-triazole,    dihydro-1,2,4-triazole, dihydro-1,3,4-triazole,    dihydro-1,2,3-oxadiazole, dihydro-1,2,4-oxadiazole,    dihydro-1,3,4-oxadiazole, dihydro-1,2,3-thiadiazole,    dihydro-1,2,4-thiadiazole, dihydro-1,3,4-thiadiazole,    dihydro-1,2,3,4-tetrazole, dihydro-1,2,3,5-tetrazole, dihydro-pyran,    dihydro-thiopyran, dihydro-thiopyran=1,1-dioxide, dihydro-pyridine,    dihydro-pyrimidine, dihydro-pyridazine, dihydropyrazine,    dihydro-1,2,3-triazine, dihydro-1,2,4-triazine,    dihydro-1,2,3,4-tetrazine, cyclopentene, cyclopentane, cyclohexene,    cyclohexane, tetrahydro-pyrrole, tetrahydro-furan,    tetrahydro-thiophene, tetrahydro-thiophene-1,1-dioxide,    tetrahydro-pyrazole, tetrahydro-imidazole, tetrahydro-isoxazole,    tetrahydro-oxazole, tetrahydro-isothiazole, tetrahydro-thiazole,    tetrahydro-1,2,3-triazole, tetrahydro-1,2,4-triazole,    tetrahydro-1,3,4-triazole, tetrahydro-1,2,3-oxadiazole,    tetrahydro-1,2,4-oxadiazole, tetrahydro-1,3,4-oxadiazole,    tetrahydro-1,2,3-thiadiazole, tetrahydro-1,2,4-thiadiazole,    tetrahydro-1,3,4-thiadiazole, tetrahydro-1,2,3,4-tetrazole,    tetrahydro-1,2,3,5-tetrazole, tetrahydro-pyran,    tetrahydro-thiopyran, tetrahydro-thiopyran-1,1-dioxide,    tetrahydro-pyridine, tetrahydro-pyrimidine, tetrahydro-pyridazine,    tetrahydro-pyrazine, tetrahydro-1,2,3-triazine,    tetrahydro-1,2,4-triazine, and tetrahydro-1,2,3,4-tetrazine;-   ring M is substituted with 0–3 R^(1a) and 0–1 carbonyl group;-   G is selected from the group:-   G₁ is absent or is selected from (CR³R^(3a))₁₋₃,    (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)C(O)(CR³R^(3a))_(u)C(O)    NR^(3b)(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)NR^(3b)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR^(3b)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂NR^(3b)(CR³R^(3a))_(w), and    (CR³R^(3a))_(u)C(O)NR^(3b)S(O)₂(CR³R^(3a))_(w), wherein u+w total 0,    1, or 2, provided that G₁ does not form a N—S, NCH₂N, NCH₂O, or    NCH₂S bond with either group to which it is attached;-   A is selected from one of the following carbocyclic and heterocyclic    groups which are substituted with 0–2 R⁴;    -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,        morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,        1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,        1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,        1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,        benzothiofuranyl, indolinyl, indolyl, benzimidazolyl,        benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl,        benzisothiazolyl, and isoindazolyl;-   B is    provided that Z and B are attached to different atoms on A;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 5–7 membered ring consisting of, in addition to the N-Q₁    group shown, carbon atoms and 0–2 heteroatoms selected from NR^(4c),    O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 5–7 membered ring to which another ring    is fused, wherein:    -   the 5–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–2 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂ and 0–1 double bonds are present        within the ring;    -   the fusion ring is phenyl or a 5–6 membered heteroaromatic        consisting of carbon atoms and 1–2 heteroatoms selected from        NR^(4c), O, and S;    -   ring Q, which includes the 5–7 membered ring and the fusion        ring, is substituted with 0–3 R^(4a);-   R^(1a) is selected from H, R^(1b), CH(CH₃)R^(1b), C(CH₃)₂R^(1b),    CH₂R^(1b), and CH₂CH₂R^(1b), provided that R^(1a) forms other than    an N-halo, N—S, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to adjacent    atoms, together with the atoms to which they are attached they form    a 5–6 membered ring consisting of: carbon atoms and 0–2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), this ring    being substituted with 0–2 R^(4b) and 0–3 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, F, Cl, Br, —CN, —CHO, CF₃,    OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b), OC(O)R², CO₂R^(2a),    S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b), C(O)NR²R^(2a),    SO₂NR²R^(2a), NR²SO₂R², phenyl substituted with 0–2 R^(4b), and 5–6    membered aromatic heterocycle consisting of carbon atoms and from    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b), provided that R^(1b)    forms other than an O—O, N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, phenyl substituted with 0–2 R^(4b), a benzyl    substituted with 0–2 R^(4b), and 5–6 membered aromatic heterocycle    consisting of: carbon atoms and 1–4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p), and substituted with 0–2    R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0–2 R^(4b), and    5–6 membered aromatic heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–2 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0–2    R^(4b), and 5–6 membered aromatic heterocycle consisting of: carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0–2 R^(4b), and 5–6 membered aromatic    heterocycle containing from 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–2 R^(4b);-   R⁴, at each occurrence, is selected from H, CH₂OR², (CH₂)₂OR², OR²,    F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), SO₂NR²R^(2a), CF₃, and CF₂CF₃;-   R^(4a), at each occurrence, is selected from H, ═O, CH₂OR², OR², F,    Br, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, CH₂NR²R^(2a), NR²R^(2a),    C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),    SO₂NR²R^(2a), and —CF₃;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, CH₂—C(O)R³, C(O)OR^(3c), CH₂—C(O)OR^(3c),    NR³C(O)R^(3a), CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂—C(O)NR³R^(3a),    SO₂NR³R^(3a), CH₂SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, CH₂NR³SO₂—C₁₋₄    alkyl, NR³SO₂-phenyl, CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃,    S(O)_(p)—C₁₋₄ alkyl, CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,    CH₂S(O)_(p)-phenyl, and CF₃;-   R^(4c), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, CH₂OR², CH₂F, CH₂Br, CH₂Cl, CH₂CN, CH₂NO₂, CH₂NR²R^(2a),    C(O)R^(2c), CH₂C(O)R^(2c), CH₂NR²C(O)R^(2b), C(O)NR²R^(2a),    CH₂C(O)NR²R^(2a), SO₂NR²R^(2a), CH₂SO₂NR²R^(2a), S(O)_(p)R^(5a),    CH₂S(O)_(p)R^(5a), CF₃, phenyl substituted with 0–1 R⁵, and benzyl    substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,    NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0–2 R⁶, naphthyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), SO₂NR²R^(2a), and    NR²SO₂C₁₋₄ alkyl.

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from:

-   J is selected from O, S, NH, and NR^(1a);-   G is selected from the group:-   G₁ is absent or is selected from CH₂, CH₂CH₂, CH₂O, OCH₂, NH, CH₂NH,    NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), NHC(O)NH, C(O)NHS(O)₂,    CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that G₁ does not    form a N—S, NCH₂N, NCH₂O, or NCH₂S bond with either group to which    it is attached;-   A is selected from indolinyl, phenyl, pyridyl, and pyrimidyl, and is    substituted with 0–2 R⁴;-   B is    provided that Z and B are attached to different atoms on A;-   provided that B is other than triazolone, quinolone, or    isoquinolone, wherein the triazolone, quinolone, and isoquinolone    groups are substituted or unsubstituted;-   Q₁ is selected from C═O and SO₂;-   ring Q is a 6–7 membered ring consisting of, in addition to the N-Q₁    group shown, carbon atoms and 0–1 heteroatoms selected from NR^(4c),    O, S, S(O), and S(O)₂, wherein:    -   0–2 double bonds are present within the ring and the ring is        substituted with 0–2 R^(4a);-   alternatively, ring Q is a 5–7 membered ring to which another ring    is fused, wherein:    -   the 5–7 membered ring consists of, in addition to the shown        amide group, carbon atoms and 0–1 heteroatoms selected from        NR^(4c), O, S, S(O), and S(O)₂ and 0–1 double bonds are present        within the ring;    -   the fusion ring is phenyl;    -   ring Q, which includes the 5–7 membered ring and the fusion        ring, is substituted with 0–2R^(4a);-   R^(1a) is selected from H, R^(1b), C(CH₃)₂R^(1b), and CH₂R^(1b),    provided that R^(1a) forms other than an N-halo, N—S, or N—CN bond;-   R^(1b) is selected from CH₃, CH₂CH₃, F, Cl, Br, —CN, CF₃, OR²,    NR²R^(2a), C(O)R^(2b), CO₂R^(2b), CO₂R^(2a), S(O)_(p)R²,    C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂R², and 5–6 membered aromatic    heterocycle consisting of carbon atoms and from 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(4b), provided that R^(1b) forms other than    an O—O, N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, phenyl substituted with 0–1 R^(4b), benzyl substituted    with 0–1 R^(4b), and 5–6 membered aromatic heterocycle consisting    of: carbon atoms and 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–1 R^(4b);-   R^(2a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0–1 R^(4b), and    5–6 membered aromatic heterocycle consisting of: carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–1 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–1 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0–1 R^(4b), and 5–6 membered aromatic    heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–1 R^(4b);-   R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0–1 R^(4b), and 5–6 membered aromatic    heterocycle containing from 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–1 R^(4b);-   R⁴, at each occurrence, is selected from OH, OR², CH₂OR², (CH₂)₂OR²,    F, Br, Cl, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, NR²R^(2a), CH₂NR²R^(2a),    (CH₂)₂NR²R^(2a), CF₃, and CF₂CF₃;-   R^(4a), at each occurrence, is selected from H, ═O, CH₂OR², OR², F,    Br, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, CH₂NR²R^(2a), NR²R^(2a), C(O)R^(2c),    NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, and CF₃;-   R^(4c), at each occurrence, is selected from H, CH₃, CH₂CH₃, phenyl    substituted with 0–1 R⁵, and benzyl substituted with 0–1 R⁵;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0–2 R⁶, naphthyl    substituted with 0–2 R⁶, and benzyl substituted with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), and SO₂NR²R^(2a).

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from:

-   J is selected from O, S, NH, and NR^(1a);-   P₄ is -G₁-G;-   M₄ is -Z-A-B;-   G is selected from:-   G₁ is absent or is selected from CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂,    C(O)NH, NHC(O), NHC(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂,    provided that G₁ does not form a N—S, NCH₂N, NCH₂O, or NCH₂S bond    with either group to which it is attached;-   A is selected from the group: indolinyl, phenyl, 2-pyridyl,    3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl,    3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;-   B is attached to a different atom on A than M and is selected from    the group:-   R^(1a) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂F, CH₂Cl, Br,    CH₂Br, —CN, CH₂CN, CF₃, CH₂CF₃, OCH₃, CH₂OH, C(CH₃)₂OH, CH₂OCH₃,    NH₂, CH₂NH₂, NHCH₃, CH₂NHCH₃, N(CH₃)₂, CH₂N(CH₃)₂, CO₂H, COCH₃,    CO₂CH₃, CH₂CO₂CH₃, SCH₃, CH₂SCH₃, S(O)CH₃, CH₂S(O)CH₃, S(O)₂CH₃,    CH₂S(O)₂CH₃, C(O)NH₂, CH₂C(O)NH₂, SO₂NH₂, CH₂SO₂NH₂, NHSO₂CH₃,    CH₂NHSO₂CH₃, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,    pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N-oxide,    imidazol-1-yl, CH₂-imidazol-1-yl, 4-methyl-oxazol-2-yl,    4-N,N-dimethylaminomethyl-oxazol-2-yl, 1,2,3,4-tetrazol-1-yl,    1,2,3,4-tetrazol-5-yl, CH₂-1,2,3,4-tetrazol-1-yl, and    CH₂-1,2,3,4-tetrazol-5-yl, provided that R^(1a) forms other than an    N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, phenyl substituted with 0–1 R^(4b), benzyl substituted    with 0–1 R^(4b), and 5 membered aromatic heterocycle consisting of:    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and substituted with 0–1 R^(4b);-   R^(2a), at each occurrence, is selected from H, CH₃, and CH₂CH₃;-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0–1 R^(4b) and    consisting of: 0–1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from OCH₃, OCH₂CH₃, CH₃, and    CH₂CH₃;-   R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,    and CH₂CH₃;-   R^(4a), at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, and    C(CH₃)₃;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂-phenyl, S(O)₂CH₃,    S(O)₂-phenyl, and CF₃;-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃, OR³,    CH₂OR³, F, Cl, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,    NR³SO₂-phenyl, S(O)₂—CH₃, S(O)₂-phenyl, CF₃, phenyl substituted with    0–2 R⁶, naphthyl substituted with 0–2 R⁶, and benzyl substituted    with 0–2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), CH₂C(O)R^(2b),    NR²C(O)R^(2b), and SO₂NR²R^(2a).

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from:

-   G is selected from:    and,-   A-B is selected from:

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from:

-   P₄ is -G; and-   A-B is selected from:

In another preferred embodiment, the present invention provides a novelcompound, wherein the compound is selected from the group:

-   1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxo-1-piperidinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide;-   1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[6-(2-oxo-1-piperidinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide;-   1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide;-   1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[6-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide;-   2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1-piperidinyl)phenyl]benzamide;-   2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1(2H)-pyridinyl)phenyl]benzamide;-   2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxotetrahydro-1(2H)-pyrimidinyl)phenyl]benzamide;-   5-chloro-N-[2-({[4-(2-oxo-1-piperidinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide;-   5-chloro-N-[2-({[4-(2-oxo-1(2H)-pyridinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide;-   5-chloro-N-[2-({[4-(2-oxotetrahydro-1(2H)pyrimidinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide;-   4-chloro-2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1-piperidinyl)phenyl]benzamide;-   4-chloro-2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1(2H)pyridinyl)phenyl]benzamide;-   4-chloro-2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxotetrahydro-1(2H)-pyrimidinyl)phenyl]benzamide;-   2-[(4-chlorobenzoyl)amino]-4-[(methylsulfonyl)amino]-N-[4-(2-oxo-1-piperidinyl)phenyl]benzamide;-   2-[(4-chlorobenzoyl)amino]-4-[(methylsulfonyl)amino]-N-[4-(2-oxo-1(2H)-pyridinyl)phenyl]benzamide;-   2-[(4-chlorobenzoyl)amino]-4-[(methylsulfonyl)amino]-N-[4-(2-oxotetrahydro-1(2H)-pyrimidinyl)phenyl]benzamide;-   5-chloro-N-[5-[(methylsulfonyl)amino]-2-({[4-(2-oxo-1-piperidinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide;-   2-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1-piperidinyl)phenyl]nicotinamide;-   3-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1-piperidinyl)phenyl]isonicotinamide;-   4-[(4-chlorobenzoyl)amino]-N-[4-(2-oxo-1-piperidinyl)phenyl]nicotinamide;-   5-chloro-N-[3-({[4-(2-oxo-1-piperidinyl)phenyl]amino}carbonyl)-4-pyridinyl]-2-pyridinecarboxamide;-   5-chloro-N-[3-({[4-(2-oxo-1(2H)-pyridinyl)phenyl]amino}carbonyl)-4-pyridinyl]-2-pyridinecarboxamide;-   5-chloro-N-[5-chloro-3-methoxy-2-({[4-(2-oxo-1(2H)-pyridinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide;-   5-chloro-N-[5-chloro-3-methoxy-2-({[4-(2-oxo-1-piperidinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide;-   methyl    2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-oxopropanoate;-   1-(3-fluoro-4-{2-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-oxoethyl}phenyl)-2(1H)-pyridinone;-   1-(4-{2-[1-(3-amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-oxoethyl}-3-fluorophenyl)-2(1H)-pyridinone;-   5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;-   1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxo-1(2H)-pyridinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide;-   5-chloro-N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-piperidine)-1-yl]benzoyl}amino)benzamide;-   5-chloro-N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)benzamide;-   N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-piperidine)-1-yl]benzoyl}amino)-5-methoxybenzamide;-   N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)-5-methoxybenzamide;-   N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-piperidin)-1-yl]benzoyl}amino)-5-methylbenzamide;-   N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)-5-methylbenzamide;-   2-(5-chloro-pyridin-2-yl)-7-methoxy-3-[4-(2-oxo-piperidin-1-yl)-phenyl]-2H-isoquinolin-1-one;-   2-(5-chloro-pyridin-2-yl)-7-methoxy-3-[4-(2-oxo-pyridin-1-yl)-phenyl]-2H-isoquinolin-1-one;-   5-chloro-N-(5-chloropyridin-2-yl)-3-methoxy-2-[4-(2-oxopiperidin-1-yl)-benzoylamino]benzamide;-   5-chloro-N-(5-chloropyridin-2-yl)-3-methoxy-2-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]benzamide;-   3-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   5-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(1,2-cis-2-{[4-(2-oxopyrazin-1(2H)-yl-benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(1,2-cis-2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   3-chloro-N-(1,2-cis-2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   5-chloro-N-(1,2-cis-2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(1,2-cis-2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   3-chloro-N-(1,2-cis-2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(2-oxopyridin-1(2H-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide;-   3-chloro-N-(3-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(4-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}tetrahydro-2H-pyran-3-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(4-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}piperidin-3-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(3-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}piperidin-4-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(4-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}pyrrolidin-3-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(4-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}tetrahydrofuran-3-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)-1H-indole-6-carboxamide;-   3-chloro-N-(1,1-dioxido-4-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}tetrahydro-3-thienyl)-1H-indole-6-carboxamide;-   3-chloro-N-(1,1-dioxido-4-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}tetrahydro-2H-thiopyran-3-yl)-1H-indole-6-carboxamide;-   3-chloro-N-(1,1-dioxido-3-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}tetrahydro-2H-thiopyran-4-yl)-1H-indole-6-carboxamide;-   N-(2-{[(3-chloro-1H-indol-6-yl)sulfonyl]methyl}cyclohexyl)-4-(2-oxopiperidin-1-yl)benzamide;-   N-(2-{[(6-chloro-2-naphthyl)sulfonyl]methyl}cyclohexyl)-4-(2-oxopiperidin-1-yl)benzamide;-   5-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)thiophene-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)-1H-indole-2-carboxamide;-   5-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)-1H-indole-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)-2-naphthamide;-   6-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)-2-naphthamide;-   2-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)quinoline-6-carboxamide;-   2-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)quinoline-6-carboxamide;-   2-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)quinoline-6-carboxamide;-   2-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)quinoline-6-carboxamide;-   2-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)quinoline-6-carboxamide;-   2-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}pentyl)quinoline-6-carboxamide;-   2-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)quinoline-6-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)-1-benzothiophene-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)thieno[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)thieno[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)thieno[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)thieno[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)thieno[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)thieno[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-(2-{[4-(2-oxopiperidin-1(2H)-yl)benzoyl]amino}cyclopentyl)thieno[2,3-b]pyridine-2-carboxamide;-   5-methoxy-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-methoxy-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-methoxy-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-methoxy-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-methoxy-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   5-methoxy-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)thiophene-2-carboxamide;-   5-methoxy-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide;-   4-methoxy-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)benzamide;-   4-methoxy-N-(2-{[4-(2-oxopiperazin-1-yl)benzoyl]amino}cyclohexyl)benzamide;-   4-methoxy-N-(2-{[4-(2-oxo-1,3-oxazinan-3-yl)benzoyl]amino}cyclohexyl)benzamide;-   4-methoxy-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)benzamide;-   4-methoxy-N-(2-{[4-(3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)benzamide;-   4-methoxy-N-(2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclopentyl)benzamide;-   4-methoxy-N-(2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclopentyl)benzamide;-   or a pharmaceutically acceptable salt form thereof.

In a preferred embodiment, when ring M is 1,2 substituted by M₄ and P₄,then either G₁ or Z is absent.

In another preferred embodiment, when ring M is 1,2 substituted by M₄and P₄ and G₁ is (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w) and u+w is 1, 2, 3,or 4, (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), or(CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w);

-   -   then Z is other than (CH₂)NR³, NR³(CH₂), (CH₂)NR³(CH₂),        (CH₂)(CH₂)NR³, NR³(CH₂)(CH₂), (CH₂)_(q)C(O)NR³(CH₂)_(q1),        (CH₂)_(q)NR³C(O) (CH₂)_(q1), (CH₂)_(q)SO₂NR³(CH₂)_(q1), or        (CH₂)_(q)NR³SO₂(CH₂)_(q1).

In another preferred embodiment, when ring M is 1,2 substituted by M₄and P₄ and Z is (CH₂)NR³, NR³(CH₂), (CH₂)NR³(CH₂), (CH₂)(CH₂)NR³,NR³(CH₂)(CH₂), (CH₂)_(q)C(O)NR³(CH₂)_(q1), (CH₂)_(q)NR³C(O)(CH₂)_(q1),(CH₂)_(q)SO₂NR³(CH₂)_(q1), or (CH₂)_(q)NR³SO₂(CH₂)_(q1);

-   -   then G₁ is other than (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w) and u+w        is 1, 2, 3, or 4, (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),        (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),        (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),        (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), or        (CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w).

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another preferred embodiment, the present invention provides a novelmethod, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, and thromboembolic disorders inthe chambers of the heart.

In another preferred embodiment, the present invention provides a novelmethod, wherein the thromboembolic disorder is selected from unstableangina, an acute coronary syndrome, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from (a) prosthetic valves or other implants, (b)indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e)hemodialysis, or (f) other procedures in which blood is exposed to anartificial surface that promotes thrombosis.

In another embodiment, the present invention provides a novel method oftreating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a thromboembolic disorder.

In another embodiment, the present invention provides a novel method,comprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a thromboembolic disorder.

In another embodiment, the present invention provides a novel method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a firstand second therapeutic agent, wherein the first therapeutic agent iscompound of the present invention or a pharmaceutically acceptable saltthereof and the second therapeutic agent is at least one agent selectedfrom a second factor Xa inhibitor, an anti-coagulant agent, ananti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent,and a fibrinolytic agent.

In another preferred embodiment, the present invention provides a novelmethod, wherein the second therapeutic agent is at least one agentselected from warfarin, unfractionated heparin, low molecular weightheparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissueplasminogen activator, modified tissue plasminogen activator,anistreplase, urokinase, and streptokinase.

In another preferred embodiment, the present invention provides a novelmethod, wherein the second therapeutic agent is at least oneanti-platelet agent.

In another preferred embodiment, the present invention provides a novelmethod, wherein the anti-platelet agent is aspirin and clopidogrel.

In another preferred embodiment, the present invention provides a novelmethod, wherein the anti-platelet agent is clopidogrel.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising:

-   -   (a) a first container;    -   (b) a pharmaceutical composition located within the first        container, wherein the composition, comprises: a first        therapeutic agent, comprising: a compound of the present        invention or a pharmaceutically acceptable salt form thereof;        and,    -   (c) a package insert stating that the pharmaceutical composition        can be used for the treatment of a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising:

-   -   (d) a second container;        wherein components (a) and (b) are located within the second        container and component (c) is located within or outside of the        second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising:

-   -   (a) a first container;    -   (b) a pharmaceutical composition located within the first        container, wherein the composition, comprises: a first        therapeutic agent, comprising: a compound of the present        invention or a pharmaceutically acceptable salt form thereof;        and,    -   (c) a package insert stating that the pharmaceutical composition        can be used in combination with a second therapeutic agent to        treat a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising:

-   -   (d) a second container;        wherein components (a) and (b) are located within the second        container and component (c) is located within or outside of the        second container.

In another embodiment, the present invention provides novel compounds asdescribed above for use in therapy.

In another embodiment, the present invention provides the use of novelcompounds as described above for the manufacture of a medicament for thetreatment of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is intended to be taken individually as itsown independent preferred embodiment. Furthermore, any element of anembodiment is meant to be combined with any and all other elements fromany embodiment to describe an additional embodiment.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.Preferably, the molecular weight is less than about 800 grams per mole.More preferably, the molecular weight is less than about 750 grams permole. Even more preferably, the molecular weight is less than about 700grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g., C═C, C═N, or N═N). The present invention,in general, does not cover groups such as N-halo, S(O)H, and SO₂H.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0–2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are amines on the compounds of this invention,these can be converted to amine N-oxides by treatment with an oxidizingagent (e.g., MCPBA and/or hydrogen peroxides) to afford other compoundsof this invention. Thus, all shown and claimed amines are considered tocover both the shown amine and its N-oxide (N→O) derivative.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₆ alkyl, is intended to include C₁,C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example −C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).Examples of haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₆ alkoxy, is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Examples of alkoxyinclude, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” isintended to include saturated ring groups, such as cyclopropyl,cyclobutyl, or cyclopentyl. C₃₋₇ cycloalkyl is intended to include C₃,C₄, C₅, C₆, and C₇ cycloalkyl groups. Alkenyl” is intended to includehydrocarbon chains of either straight or branched configuration and oneor more unsaturated carbon-carbon bonds that may occur in any stablepoint along the chain, such as ethenyl and propenyl. C₂₋₆ alkenyl isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. “Alkynyl” isintended to include hydrocarbon chains of either straight or branchedconfiguration and one or more triple carbon-carbon bonds that may occurin any stable point along the chain, such as ethynyl and propynyl. C₂₋₆Alkynyl is intended to include C₂, C₃, C₄, C₅, and C₆ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic ring, any ofwhich may be saturated, partially unsaturated, or unsaturated(aromatic). Examples of such carbocycles include, but are not limitedto, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.As shown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when oneor more carbon atoms link two non-adjacent carbon atoms. Preferredbridges are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selectedfrom the group consisting of N, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized (i.e., NO and S(O)_(p)). The nitrogen atom may be substitutedor unsubstituted (i.e., N or NR wherein R is H or another substituent,if defined). The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1. Asused herein, the term “aromatic heterocyclic group” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O and S. The nitrogen atom maybe substituted or unsubstituted (i.e., N or NR wherein R is H or anothersubstituent, if defined). The nitrogen and sulfur heteroatoms mayoptionally be oxidized (i.e., N→O and S(O)_(p)). It is to be noted thattotal number of S and O atoms in the aromatic heterocycle is not morethan 1. Bridged rings are also included in the definition ofheterocycle. A bridged ring occurs when one or more atoms (i.e., C, O,N, or S) link two non-adjacent carbon or nitrogen atoms. Preferredbridges include, but are not limited to, one carbon atom, two carbonatoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogengroup. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of the presentinvention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that there presentlyrecited compounds do not contain a N-halo, S(O)₂H, or S(O)H group.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor Xa. “Therapeutically effectiveamount” is also intended to include an amount of the combination ofcompounds claimed that is effective to inhibit factor Xa. Thecombination of compounds is preferably a synergistic combination.Synergy, as described, for example, by Chou and Talalay, Adv. EnzymeRegul. 1984, 22:27–55, occurs when the effect (in this case, inhibitionof factor Xa) of the compounds when administered in combination isgreater than the additive effect of the compounds when administeredalone as a single agent. In general, a synergistic effect is mostclearly demonstrated at sub-optimal concentrations of the compounds.Synergy can be in terms of lower cytotoxicity, increased antithromboticeffect, or some other beneficial effect of the combination compared withthe individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene and Wuts (Protective Groups In Organic Synthesis,Wiley and Sons, 1991). All references cited herein are herebyincorporated in their entirety herein by reference.

The synthesis of compounds of the present invention that involves theusage of intermediate A-B is accomplished via standard methods known tothose skilled in the art. The general route that involves this type ofmethodology is outlined in Scheme 1.

A-B intermediates can be obtained via Ullman or Buchwald methodologiesthat are outlined in the schemes below.

Intermediates A-B wherein the B group contains an oxidizable group canbe obtained by oxidation, e.g. S to SO and SO₂. The pyridone analogs canalso be prepared via the Ullman methodology. The Ullman coupling canalso be applied to prepare urea analogs shown in scheme 3.

Piperidone A-B analogs can be prepared via the method outlined in scheme4.

Aminopyridyl and aminopyrimidyl A-B analogs (see structures below) canalso be prepared using routes similar to those of scheme 2–4.

Piperidone A-B intermediates shown above can also be can be furtherelaborated to afford other compounds of the present invention bynumerous methods known to those skilled in the art (e.g., see scheme 5).

Additional A-B intermediates can be synthesized by the chemicalmanipulation of the amino functionality of the compounds described above(see Scheme 6).

Other possible A-B intermediates can be synthesized by the methods shownin scheme 7. The iodo-ester intermediate can be subjected to the Ullmanand/or the Buchwald coupling methodologies to afford A-B intermediates.These intermediates in turn can be homologated via the Arndt Eistertmethodology to afford other A-B intermediates. Alternatively, the esterfunctionality can be reduced to the alcohol that in turn can beconverted to a variety of A-B intermediates by procedures known to thoseskilled in the art.

Non-aromatic intermediates as shown in scheme 8 can be synthesized viaprocedures known to those skilled in the art. These intermediates canthan be further manipulated to incorporate R^(4a) via procedurespreviously described.

Alternative non-aromatic intermediates can be synthesized via proceduresknown to those skilled in the art, e.g., see scheme 9. Theseintermediates can also be further manipulated to incorporate R^(4a) viaprocedures described previously. Further modifications of the esterfunctionality can be done via procedures described above.

Schemes 2–9 describe methods of preparing A-B intermediates that canthen be coupled with other appropriate intermediates to form compoundsof the present invention. The halogenated intermediates illustrated inthe schemes shown above when subjected to the Ullman or theBuchwald-Goldman coupling methodologies afford compounds of thisinvention.

In cases wherein an intermediate of the present invention has a reactivegroup, the Ullman or the Buchwald-Goldman couplings are usuallyperformed at an earlier stage of the synthesis. This intermediate may bemodified later by those skilled in the art to afford compounds of thepresent invention (see Scheme 10).

Compounds of the present invention wherein the B subunit of the A-Bsubstituent is a hetero substituted cyclic amide can also undergo anUllman or a Buchwald coupling to afford compounds of the presentinvention.

Likewise compounds of the present invention wherein B is a cyclic ureacan also be prepared via the Ullman or Buchwald methodology described inscheme 12. Further elaboration by those skilled in the art would providecompounds of the present invention.

An alternate approach to compounds of the present invention wherein theB subunit of the A-B group of formula I is a bicycle is shown in scheme13. Further elaboration by those skilled in the art would providecompounds of the present invention.

Schemes 2–13 describe how to make the A-B moieties of the presentinvention and how to couple them to prepare compounds of the presentinvention. In the above schemes, the Z group may or may not be presentdepending on how the A-B group is coupled. The coupling portion of theA-B group could (a) be displaced by the incoming Z or M group, (b)become the Z group, or (c) be incorporated into ring M.

The remaining portions of the compounds of the present invention,G-G₁-P-M-Z, G-G₁-M-P-Z, G-G₁-P-M, G-G₁-M-P, G-G₁-M-Z, and G-G₁-M, can beprepared using methods known to those of ordinary skill in the art. Allof the following patents and publications are incorporated herein byreference. For compounds wherein ring P is absent and ring M is a 5-,6-, or 7-membered ring, one of ordinary skill in the art can look toU.S. Pat. No. 5,939,418, U.S. Pat. No. 5,925,635, U.S. Pat. No.6,057,342, U.S. Pat. No. 6,187,797, U.S. Pat. No. 6,020,357, U.S. Pat.No. 6,060,491, U.S. Pat. No. 5,998,424, U.S. Pat. No. 6,191,159,WO98/57951, WO99/32454, WO00/039108, WO00/059902, WO01/32628,WO01/005785, U.S. Ser. No. 09/892,319, U.S. Ser. No. 60/313,552, U.S.Ser. No. 60/246,108, and U.S. Ser. No. 09/887,936 for starting materialsand intermediates to which the present B and/or A-B groups can becoupled. For compounds wherein ring P is fused to ring M (i.e., abicyclic moiety is present), one of ordinary skill in the art can lookto WO00/39131, U.S. Ser. No. 60/246,125, U.S. Ser. No. 60/292,665, U.S.Ser. No. 60/278,173, U.S. Ser. No. 60/278,165, and U.S. Ser. No.09/887,850 for starting materials and intermediates to which the presentB and/or A-B groups can be coupled.

For compounds wherein G is a ring substituted with a basic moiety, oneof ordinary skill in the art can look to U.S. Pat. No. 5,939,418, U.S.Pat. No. 5,925,635, U.S. Pat. No. 6,057,342, U.S. Pat. No. 6,187,797,U.S. Pat. No. 6,020,357, U.S. Pat. No. 6,060,491, U.S. Pat. No.6,191,159, WO98/57951, WO99/32454 WO00/059902, WO01/32628, WO00/39131,U.S. Ser. No. 09/892,319, U.S. Ser. No. 60/313,552, U.S. Ser. No.60/246,108, U.S. Ser. No. 60/246,125, U.S. Ser. No. 60/292,665, U.S.Ser. No. 60/278,173, and U.S. Ser. No. 60/278,165 for starting materialsand intermediates to form the present G-G₁-P-M-Z, G-G₁-M-P-Z,G-G₁-P-M-Z-A, and/or GG₁-M-P-Z-A groups to which the present B and/orA-B groups can be coupled. For compounds wherein G is a ring substitutedwith a non-basic group, one of ordinary skill in the art can look toU.S. Pat. No. 5,998,424, WO00/39131, WO00/059902, WO01/32628, U.S. Ser.No. 09/892,319, U.S. Ser. No. 60/313,552, U.S. Ser. No. 60/246,108, U.S.Ser. No. 60/246,125, U.S. Ser. No. 60/292,665, U.S. Ser. No. 60/278,173,and U.S. Ser. No. 60/278,165 for starting materials and intermediates toform the present G-G₁-P-M-Z, G-G₁-M-P-Z, G-G₁-P-M-Z-A, and/orG-G₁-M-P-Z-A groups to which the present B and/or A-B groups can becoupled. For compounds wherein G is a bicyclic moiety, one of ordinaryskill in the art can look to WO98/57951 WO00/039108, WO00/39131, U.S.Ser. No. 09/892,319, U.S. Ser. No. 60/313,552, U.S. Ser. No. 60/246,108,U.S. Ser. No. 60/246,125, U.S. Ser. No. 60/292,665, U.S. Ser. No.60/278,173, and U.S. Ser. No. 60/278,165 for starting materials andintermediates to form the present G-G₁-P-M-Z, G-G₁-M-P-Z, G-G₁-P-M-Z-A,and/or G-G₁-M-P-Z-A groups to which the present B and/or A-B groups canbe coupled. For compounds wherein A is an indoline or similar bicycle,one of ordinary skill in the art can look to WO01/005785 for startingmaterials and intermediates to which the present B group can be coupledor from which the present A-B groups can be formed. Scheme 14illustrates some of the numerous pyrrole intermediates that can be usedto prepare compounds of the present invention (R^(z) is the point ofattachment for Z-A-B and can be H, a protecting group, a groupmodifiable to Z or Z-A, Z, Z-A, or A). These intermediates are describedin the above-noted patents and publications.

Scheme 15 illustrates some of the numerous imidazole, triazole, andtetrazole intermediates that can be used to prepare compounds of thepresent invention. These intermediates are described in the above-notedpatents and publications. In Scheme 15, V is nitro, amino, thio,hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid,or halide. In Scheme 15, U is aldehyde, ester, acid, amide, amino, thio,hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylenehalide.

Scheme 16 shows some of the numerous pyrazole intermediates that can beused to prepare compounds of the present invention. These intermediatesare described in the above-noted patents and publications.

Scheme 17 depicts some of the numerous oxazole, thiazole, isoxazole,oxadiazole, and thiadiazole intermediates that can be used to preparecompounds of the present invention. These intermediates are described inthe above-noted patents and publications. In Scheme 17, V is nitro,amino, ester, or acid.

Scheme 18 illustrates two intermediates useful for making a compound ofthe present invention wherein ring P is fused to ring M. Scheme 18 alsoillustrates a number of bicyclic compounds that can be made from theseintermediates or derivatives thereof. These intermediates and theirmodification are described in the above-noted patents and publications.

Scheme 19 depicts another intermediate useful for making a compound ofthe present invention wherein ring P is fused to ring M. Scheme 19 alsoillustrates a number of bicyclic compounds that can be made from thisintermediate or derivatives thereof (e.g., the correspondingcyclohexenone). In Scheme 19, U is OH or morpholine and V is H orC(O)R^(1a). This intermediate, derivatives thereof, and theirmodification are described in the above-noted patents and publications.

Scheme 20 shows another intermediate useful for making a compound of thepresent invention wherein ring P is fused to ring M. Scheme 20 alsoillustrates a number of bicyclic compounds that can be made from thisintermediate or derivatives thereof. This intermediate, derivativesthereof, and their modification are described in the above-noted patentsand publications.

Scheme 21 illustrates a number of other bicyclic rings that areconsidered to be part of the present bicyclic group, rings P-M. Scheme21 also describes a method of converting the shown rings to compounds ofthe present invention. As one of ordinary skill in the art wouldrecognize, this method would be applicable to other heterobicyclics notshown.

Other useful pyrazole intermediates wherein G₁ is an amide areexemplified in Scheme 22. Compounds of the present invention wherein theG₁ group is other than an amide can be easily manipulated to otherlinker functionalities according to the methodologies known in the art,including the methodologies outlined in WO98/28269 and WO98/28282, thecontents of both are incorporated herein by reference.

Scheme 23 depicts some of the numerous 6-membered aromatic ringintermediates that can be used to prepare compounds of the presentinvention. These intermediates are described in the above-noted patentsand publications. In Scheme 23, V is nitro, protected sulfonamide, orester group and is a precursor of group Z of the present invention.

Benzo-fused dihydro-pyridone intermediates of the present invention canbe prepared from readily available starting materials as shown in Scheme24.

Other benzo-bicyclic compounds can be obtained as shown in schemes 25and 26.

Intermediates A-B of the present invention wherein A is indoline can beprepared as shown in scheme 27. This type of intermediate can then beattached to the remainder of the desired compound as describedpreviously. Alternatively, the indoline can be attached to the otherhalf of the desired compound prior to formation of the lactam ring.

Compounds of the present invention wherein ring P is absent and ring Mis a six-membered ring can be obtained as shown in scheme 28. Thesetypes of compounds can be obtained from commercially availableanthranilic acids or their anthranilates. Anthranilic acids or theirnitro precursors can be coupled with a suitable B-A-V (wherein V is aamino functionality) in presence of a base such as triethyl amine,pyridine, or DMAP. Subsequent coupling with an appropriate acid chlorideor aniline or aminopyridyl should afford compounds of the presentinvention.

In an analogous fashion the anthranilates can be coupled with a suitableamine, aniline, or aminopyrimidyl to afford the corresponding benzamide.The benzamides can then be coupled with an appropriate B-A-V (wherein Vis a acid chloride derivative, an alkyl halide, or a sulfonyl chloride)to afford additional compounds of the present invention (see scheme 29).

Commercially available ring M derivatives bearing a nitro and aminofunctionality can also be derivatized as shown above to afford bisamideanalogs. In this case, coupling of the aniline with B-A-V (wherein V isan acid chloride, a sulfonyl chloride, or an alkylhalide) affords anintermediate that can be subjected to treatment with an appropriate G-U(wherein U is either a acid chloride or an alkyl halide) in presence ofa suitable base such as DMAP. It should be noted that the order ofaddition of B-A-V and G-U can be reversed to obtain other compounds ofthe present invention (see scheme 30).

It should be noted that the syntheses shown above could be modified touse coupling intermediates such as Iodo-A-V, wherein V is an acidchloride, amino, alkylhalide, or sulfonyl chloride. These in turn couldbe coupled to a G-U group. The iodo intermediate could then be subjectedto Ullman or Buchwald coupling as described previously to affordcompounds of the present invention. The iodo intermediate could also beconverted to an amine via standard Buchwald conditions to afford thecorresponding anilino intermediate. This in turn could be coupled aspreviously described to afford compounds of the present invention.

When M is a non-aromatic ring, the compounds of this invention withgeneral structure of Formula I can be synthesized by using similarmethods as described previously and by those skilled in the art. Onediastereomer of a compound of Formula I may display better activitycompared with the others. Thus, the following stereochemistries areconsidered to be a part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Wilen, S. H. Tables of Resolving Agentsand Optical Resolutions 1972, 308 pp or using enantiomerically pureacids and bases. A chiral compound of Formula I may also be directlysynthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen,E. Acc. Chem. Res. 2000, 33, 421–431 or using other enantio- anddiastereo-selective reactions and reagents known to one skilled in theart of asymmetric synthesis.

Utility

The compounds of this invention are inhibitors of factor Xa and areuseful as anticoagulants for the treatment or prevention ofthromboembolic disorders in mammals (i.e., factor Xa-associateddisorders). In general, a thromboembolic disorder is a circulatorydisease caused by blood clots (i.e., diseases involving fibrinformation, platelet activation, and/or platelet aggregation). The term“thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart. The term “thromboembolic disorders” as used herein alsoincludes specific disorders selected from, but not limited to, unstableangina or other acute coronary syndromes, first or recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom (a) prosthetic valves or other implants, (b) indwelling catheters,(c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis. It is noted that thrombosis includes occlusion(e.g. after a bypass) and reocclusion (e.g., during or afterpercutaneous transluminal coronary angioplasty). The thromboembolicdisorders may result from conditions including but not limited toatherosclerosis, surgery or surgical complications, prolongedimmobilization, arterial fibrillation, congenital thrombophilia, cancer,diabetes, effects of medications or hormones, and complications ofpregnancy. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Diapharma/Chromogenix, West Chester, Ohio) was measured both inthe absence and presence of compounds of the present invention.Hydrolysis of the substrate resulted in the release of pNA, which wasmonitored spectrophotometrically by measuring the increase in absorbanceat 405 nm. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,K_(m), for substrate hydrolysis was determined at 25° C. using themethod of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2–0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM–1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 min and the velocities(rate of absorbance change vs. time) were measured in the time frame of25–30 min. The following relationship was used to calculate K_(i)values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))where:

-   -   v_(o) is the velocity of the control in the absence of        inhibitor;    -   v_(s) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   K_(i) is the dissociation constant of the enzyme:inhibitor        complex;    -   S is the concentration of substrate;    -   K_(m) is the Michaelis constant.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM. Using the methodologydescribed above, a number of compounds of the present invention werefound to exhibit K_(i)'s of ≦10 μM, thereby confirming the utility ofthe compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2–3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing that contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After 40 min, the shunt is disconnected and thesilk thread covered with thrombus is weighed. Test agents or vehiclewill be given (i.v., i.p., s.c., or orally) prior to the opening of theAV shunt. The percentage inhibition of thrombus formation is determinedfor each treatment group. The ID₅₀ values (dose which produces 50%inhibition of thrombus formation) are estimated by linear regression.

The compounds of the present invention may also be useful as inhibitorsof serine proteases, notably human thrombin, Factor VIIa, Factor IXa,Factor XIa, urokinase, plasma kallikrein, and plasmin. Because of theirinhibitory action, these compounds are indicated for use in theprevention or treatment of physiological reactions, blood coagulationand inflammation, catalyzed by the aforesaid class of enzymes.Specifically, the compounds have utility as drugs for the treatment ofdiseases arising from elevated thrombin activity such as myocardialinfarction, and as reagents used as anticoagulants in the processing ofblood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289–18297 (1990),herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 min of incubation, thrombin activity was assayedby monitoring the rate of increase in absorbance at 405 nm that arisesowing to substrate hydrolysis. Inhibition constants were derived fromreciprocal plots of the reaction velocity as a function of substrateconcentration using the standard method of Lineweaver and Burk. Usingthe methodology described above, some compounds of this invention wereevaluated and found to exhibit a K_(i) of less than 10 μM, therebyconfirming the utility of the compounds of the present invention aseffective thrombin inhibitors.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to treat a thromboembolic condition or disease.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thata compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Additional therapeutic agents include other anti-coagulant orcoagulation inhibitory agents, anti-platelet or platelet inhibitoryagents, thrombin inhibitors, thrombolytic or fibrinolytic agents,anti-arrythmic agents, anti-hypertensive agents, calcium channelblockers (L-type and T-type), cardiac glycosides, diruetics,mineralocorticoid receptor antagonists, phospodiesterase inhibitors,cholesterol/lipid lowering agents and lipid profile therapies,anti-diabetic agents, anti-depressants, anti-inflammatory agents(steroidal and non-steroidal), anti-osteoporosis agents, hormonereplacement therapies, oral contraceptives, anti-obesity agents,anti-anxiety agents, anti-proliferative agents, anti-tumor agents,anti-ulcer and gastroesophageal reflux disease agents, growth hormoneand/or growth hormone secretagogues, thyroid mimetics (including thyroidreceptor antagonist), anti-infective agents, anti-viral agents,anti-bacterial agents, and anti-fungal agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin and heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin), synthetic pentasaccharide,direct acting thrombin inhibitors including hirudin and argatrobanaswell as other factor Xa inhibitors such as those described in thepublications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example byinhibiting the aggregation, adhesion or granular secretion of platelets.Agents include, but are not limited to, the various known non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,sulindac, indomethacin, mefenamate, droxicam, diclofenac,sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts orprodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA)and piroxicam are preferred. Other suitable platelet inhibitory agentsinclude IIb/IIIa antagonists (e.g., tirofiban, eptifibatide, andabciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g.,dipyridamole), and pharmaceutically acceptable salts or prodrugsthereof.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferably antagonists of the purinergic receptors P₂Y₁ andP₂Y₁₂, with P₂Y₁₂ being even more preferred. Preferred P₂Y₁₂ receptorantagonists include ticlopidine and clopidogrel, includingpharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is aneven more preferred agent. Ticlopidine and clopidogrel are alsopreferred compounds since they are known to be gentle on thegastro-intestinal tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin, argatroban, andmelagatran, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal α-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin.

The term thrombolytics or fibrinolytic agents (or thrombolytics orfibrinolytics), as used herein, denote agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (natural orrecombinant) and modified forms thereof, anistreplase, urokinase,streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIainhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), alpha2-antiplasmin inhibitors, and anisoylatedplasminogen streptokinase activator complex, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in EP 028,489, the disclosure ofwhich is hereby incorporated herein by reference herein. The termurokinase, as used herein, is intended to denote both dual and singlechain urokinase, the latter also being referred to herein asprourokinase.

Examples of suitable anti-arrythmic agents for use in combination withthe present compounds include: Class I agents (such as propafenone);Class II agents (such as carvadiol and propranolol); Class III agents(such as sotalol, dofetilide, amiodarone, azimilide and ibutilide);Class IV agents (such as ditiazem and verapamil); K⁺ channel openerssuch as I_(Ach) inhibitors, and I_(Kur) inhibitors (e.g., compounds suchas those disclosed in WO01/40231).

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include: alpha adrenergicblockers; beta adrenergic blockers; calcium channel blockers (e.g.,diltiazem, verapamil, nifedipine, amlodipine and mybefradil); diruetics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone); renin inhibitors; ACEinhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); DualET/AII antagonist (e.g., compounds disclosed in WO00/01389); neutralendopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat, gemopatrilat and nitrates).

Examples of suitable calcium channel blockers (L-type or T-type) for usein combination with the compounds of the present invention includediltiazem, verapamil, nifedipine, amlodipine and mybefradil.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable diruetics for use in combination with the compoundsof the present invention include: chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, and spironolactone.

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includesprionolactone and eplirinone.

Examples of suitable phospodiesterase inhibitors for use in combinationwith the compounds of the present invention include: PDE III inhibitors(such as cilostazol); and PDE V inhibitors (such as sildenafil).

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include: HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin)); squalene synthetaseinhibitors; fibrates; bile acid sequestrants (such as questran); ACATinhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterolabsorption inhibitors; and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: biguanides (e.g.,metformin); glucosidase inhibitors (e.g., acarbose); insulins (includinginsulin secretagogues or insulin sensitizers); meglitinides (e.g.,repaglinide); sulfonylureas (e.g., glimepiride, glyburide andglipizide); biguanide/glyburide combinations (e.g., glucovance),thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1(GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-depressant agents for use in combination withthe compounds of the present invention include nefazodone andsertraline.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include: prednisone;dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors;cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen;celecoxib; and/or rofecoxib.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate andraloxifene.

Examples of suitable hormone replacement therapies for use incombination with the compounds of the present invention include estrogen(e.g., congugated estrogens) and estradiol.

Examples of suitable anti-coagulants for use in combination with thecompounds of the present invention include heparins (e.g., unfractionedand low molecular weight heparins such as enoxaparin and dalteparin).

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include orlistat and aP2 inhibitors(such as those disclosed in WO00/59506).

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Examples of suitable anti-ulcer and gastroesophageal reflux diseaseagents for use in combination with the compounds of the presentinvention include famotidine, ranitidine, and omeprazole.

Administration of the compounds of the present invention (i.e., a firsttherapeutic agent) in combination with at least one additionaltherapeutic agent (i.e., a second therapeutic agent), preferably affordsan efficacy advantage over the compounds and agents alone, preferablywhile permitting the use of lower doses of each (i.e., a synergisticcombination). A lower dosage minimizes the potential of side effects,thereby providing an increased margin of safety. It is preferred that atleast one of the therapeutic agents is administered in a sub-therapeuticdose. It is even more preferred that all of the therapeutic agents beadministered in sub-therapeutic doses. Sub-therapeutic is intended tomean an amount of a therapeutic agent that by itself does not give thedesired therapeutic effect for the condition or disease being treated.Synergistic combination is intended to mean that the observed effect ofthe combination is greater than the sum of the individual agentsadministered alone.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but not in thepresence of a compound of the present invention, then one would concludefactor Xa was present.

Compounds of the present invention may further be useful as diagnosticagents and adjuncts. For example, the present compounds may be useful inmaintaining whole and fractionated blood in the fluid phase such asrequired for analytical and biological testing.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic disorder (as definedpreviously). In another embodiment, the package insert states that thepharmaceutical composition can be used in combination (as definedpreviously) with a second therapeutic agent to treat a thromboembolicdisorder. The article of manufacture can further comprise: (d) a secondcontainer, wherein components (a) and (b) are located within the secondcontainer and component (c) is located within or outside of the secondcontainer. Located within the first and second containers means that therespective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/min during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 mg to about 100 mg of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5–95% by weight basedon the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesiumstearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 mg of the active ingredient. The capsules should bewashed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 mg of active ingredient, 0.2 mg of colloidal silicondioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatingsmay be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P, and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 mg of the compound of Formula I and about 1 to 7.5 mg of the secondanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the compounds of this invention generally may be present in anamount of about 5 to 10 mg per dosage unit, and the secondanti-coagulant in an amount of about 1 to 5 mg per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 mg of the compound ofFormula I and about 50 to 150 mg of the anti-platelet agent, preferablyabout 0.1 to 1 mg of the compound of Formula I and about 1 to 3 mg ofantiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are administered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1 mg ofthe compound of Formula I, per kilogram of patient body weight and, inthe case of the thrombolytic agents, the usual dosage of the thrombolyicagent when administered alone may be reduced by about 70–80% whenadministered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are affordedfor illustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 13-Methoxy-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7-H-pyrazolo[3,4-c]pyridin-7-one

Part A. To a solution of 1.91 g of DMAP in 10 mL of methylene chloridewas added 1.45 mL of trichloroacetyl chloride at 0° C. After stirring atrt for 30 min, 1.0 g of1-(4-iodophenyl)-3-(4-morpholinyl)-5,6-dihydro-2(1H)-pyridinone wasadded. The reaction mixture was refluxed overnight, then quenched withwater, extracted with ether. The organic layers were dried over Na₂SO₄and concentrated to dryness to provide the crude product that was usedin the next step without further purification.

Part B. The crude material from above in a mixture of 20 mL of ether, 1mL of water and 1 mL of conc. HCl was heated to reflux (oil bath 65° C.)for 3 h. The mixture was then allowed to cool to rt and filtered tocollect the product as a solid (0.97 g, 81% in 2 steps). ¹H NMR(DMSO-d₆, 300 MHz) δ 7.79 (2H, d, J=8.7 Hz), 7.25 (2H, d, J=8.7 Hz),3.89 (2H, t, J=6.2 Hz), 2.92 (2H, t, J=6.2 Hz) ppm.

Part C. A mixture of the “trione” made above (0.5 g, 1.09 mmol),p-methoxyphenylhyrazine HCl salt (0.152 g, 1.09 mmol) in 20 mL of THFwas treated with 0.30 mL of triethylamine at rt overnight. To thereaction mixture was added 20 mL of 1N HCl. The resulting mixture wasrefluxed for 2 h. After cooling to rt, the compound was collected byfiltration (0.42 g, 84%). ¹H NMR (DMSO-d₆, 300 MHz) δ 8.78 (1H, s), 8.26(2H, m), 7.92 (2H, m), 7.72 (2H, m), 7.46 (2H, m), 4.59 (2H, m) 4.09(3H, s), 3.42 (2H, m) ppm. LRMS (AP⁺) 462 (M₊+1).

Part D. To a solution of the hydroxy compound (1.78 g, 3.86 mmol) in 20mL of DMF was added sodium hydride (232 mg, 60%, 5.79 mmol) at 0° C. Themixture was stirred at rt for 30 min. To the reaction mixture was addedMeI (0.36 mL, 5.79 mmol). The reaction was stirred at rt overnight, thenquenched with water, extracted with ether. The organic layers were driedover Na₂SO₄, concentrated to dry. The residue was purified by columnchromatography to yield-(4-iodophenyl)-3-methoxy-1-(4-methoxyphenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(1.67 g, 91%). ¹H NMR (DMSO-d₆, 300 MHz) δ 7.67 (2H, d, J=8.8 Hz), 7.43(2H, d, J=9.1 Hz), 7.07 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=9.1 Hz), 4.02(5H, m, with a three proton singlet), 3.80 (3H, s), 2.90 (2H, d, J=6.6Hz) ppm.

Part E. An oven-dried flask was charged with 0.28 g of6-(4-iodophenyl)-3-methoxy-1-(4-methoxyphenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,90 mg of δ-valerolactam, and 70 mg of anhydrous (powdered) potassiumcarbonate. The solids were dissolved in 3 mL of degassed DMSO, afterwhich 20 mg of copper (I) iodide was added. The flask was fitted with areflux condenser and heated to 120° C. while stirring for 12 h. Thereaction was cooled to rt, then quenched by the addition of water.Product was extracted into ethyl acetate, which was then dried overNa₂SO₄ and concentrated to yield a yellow solid. The residue waspurified by HPLC to yield 50 mg of the title compound as a TFA salt (15%yield). ¹H NMR (MeOH-d₄, 300 MHz) δ 7.38 (2H, d, J=1.5 Hz), 7.35 (2H, d,J=1.5 Hz), 7.28 (2H, d, J=10 Hz), 6.92 (2H, d, J=10 Hz), 4.06 (2H, t,J=7.0 Hz), 3.96 (3H, s), 3.79 (3H, s), 3.64 (2H, t, J=5.9 Hz), 2.89 (3H,t, J=7.0), 2.49 (3H, t, J=5.9 Hz), 1.94 (4H, m) ppm.

Example 21-(4-methoxyphenyl)-3-[(methylamino)methyl]-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part A. An oven-dried flask with stir-bar was charged with vacuum-ovendried lithium chloride (1.6 g, 38 mmol) and potassium borohydride (2.1g, 38 mmol). The solids were dissolved in 60 mL dry THF while the systemwas flushed with N₂. The mixture was stirred at rt for 30 min beforecooling to 0° C. A solution of ethyl6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(9 g, 17 mmol) dissolved in 40 mL of dry THF was slowly added to thestirring suspension, and the reaction was continued for 12 h, beginningat 0° C. and gradually warming to rt. The reaction was quenched by theaddition of water and a small amount of 1N HCl aqueous solution untilthe pH was 7.0. The product crashed out of solution and was filtered offand vacuum dried to afford 6.9 g of the corresponding alcohol (83%yield). LRMS (ES⁺) 476 (M+H)⁺.

Part B. A vacuum-dried flask with stir-bar containing the alcohol (850mg, 1.8 mmol) synthesized above was charged with 10 mL dichloromethaneand purged with N₂ before cooling to 0° C. To the stirring solution wasadded phosphorus tribromide (0.170 mL, 1.8 mmol) dropwise. The reactionwas stirred for 12 h beginning at 0° C. and then warmed gradually to rt.The reaction was diluted with dichloromethane, and then quenched withaqueous NaHCO₃ solution. The organic phase was washed with brine anddried over Na₂SO₄ before concentration to yield 1 g of the correspondingbromide (quantitative yield). LRMS (ES⁺) 538, 540 (M, M+2)⁺.

Part C. The bromide (1 g, 2 mmol) from the reaction above was added toan oven-dried flask as a solution in 10 mL dry THF. A stir-bar and asolution of methylamine (5 mL, 10 mmol in THF) was added. The reactionwas stirred overnight at rt. Water was added to the reaction solutionand the product was extracted with ethyl acetate. The organics wereconcentrated to yield 850 mg (85% yield) of the desired compound as anoil. LRMS (ES⁺) 489 (M+H)⁺.

Part D. A vacuum dried flask with stir-bar containing 850 mg (1.7 mmol)of the amine from the reaction above was charged with di-tert-butyldicarbonate (860 mg, 3.5 mmol), 4-DMAP (10 mg, 0.09 mmol, triethylamine(1.2 mL, 8.7 mmol), and 10 mL of dichloromethane. The reaction wasstirred at rt for 10 min and another 1.2 mL of triethylamine was addedto the reaction before stirring for 12 h. The reaction was quenched bythe addition of dichloromethane and 1N HCl aqueous solution. Theorganics were separated and washed with brine, then dried over Na₂SO₄.The solution was filtered and concentrated by rotovap to yield 490 mg(48% yield) of the Boc-protected amine. 1H NMR (CDCl₃, 300 MHz) δ 7.66(2H, d, J=8.8 Hz), 7.45 (2H, d, J=8.8 Hz), 7.08 (2H, d, J=8.7 Hz), 6.91(2H, d, J=8.7 Hz), 4.56 (2H, s), 4.05 (2H, t, J=6.6 Hz), 3.81 (3H, s),2.88 (2H, t, J=6.6 Hz), 2.85 (3H, s), 1.49 (9H, s) ppm.

Part E. An oven-dried flask with stir-bar was charged with thepreviously synthesized N-Boc amino compound (100 mg, 0.17 mmol),δ-valerolactam (20 mg, 20 mmol),4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 50 mmol),palladium (II) acetate (8 mg, 30 mmol), and cesium carbonate (80 mg, 30mmol). The solids were dissolved in previously degassed 1,4-dioxane (6mL). The flask was fitted with a reflux condenser and heated to 80° C.while stirring for 12 h. The reaction was quenched by addition of waterand extracted into ethyl acetate. The organic solution was washed withbrine and dried over Na₂SO₄ before concentration in vacuo to afford 45mg of the corresponding lactam (47% yield). LRMS (ES⁺) 560 (M+H)⁺.

Part F. A solution of the lactam (45 mg, 80 mmol) dissolved inchloroform (4 mL) was transferred into an oven-dried flask with stir-barand purged with N₂ before the addition of TFA (1 mL, 13 mmol) dropwisevia syringe. The reaction was stirred at rt for 12 h, then diluted withdicholoromethane and aqueous NaHCO₃. The organic solution was washedwith brine and dried over Na₂SO₄ before concentration and purificationby HPLC to afford 13 mg as a TFA salt (26% yield). LRMS (ES⁺) 460(M+H)⁺. ¹H NMR (CDCl₃, 300 MHz) δ 7.43 (2H, d, J=8.8 Hz), 7.38 (2H, d,J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 4.82 (2H, s),4.32 (2H, s), 4.12 (2H, t, J=6.6 Hz), 3.81 (3H, s), 3.65 (2H, t, J=5.4Hz), 3.06 (2H, t, J=6.6 Hz), 2.81 (3H, s), 2.49 (2H, t, J=6.2 Hz), 1.94(4H, t, J=3.3 Hz) ppm.

Example 31-(3-chloro-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one

Part A. 3-chloro-4-fluorophenyl hydrazine (5.00 g, 31.14 mmol) and1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione (12.8 g, 31.14mmol) were added together with 120 mL of ethanol and 4 mL ofhydrochloric acid (12 M). The mixture was stirred at reflux under N₂ forovernight. The reaction was cooled down to rt. The solvents wereremoved, and the residue was dissolved in EtOAc (200 mL) and washed withwater (100 mL×2) and brine (50 mL). It was then dried over Na₂SO₄ andconcentrated. The residue was purified via flash chromatography onsilica gel using 4:1 hexane:ethylacetate to give1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-oneas a brown solid (12.5 g, 75% yield). LRMS (AP⁺): 536.1 (M+H)⁺. ¹H NMR(CDCl₃) δ 7.72 (d, 2H), 7.67–7.64 (m, 1H), 7.49–7.44 (m, 1H), 7.19 (t,3H), 7.06 (d, 2H), 4.12 (t, 2H), 3.17 (t, 2H).

Part B.1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one(0.54 g, 1.0 mmol), δ-valerolactam (0.12 g, 1.2 mmol),1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), K₃PO₄ (0.42 g, 2 mmol) andCuI (2 mg, 0.01 mmol) were added to 5 mL of 1,4-dioxane. The mixture wasdegassed under argon and stirred at 110° C. under N₂ for 48 h. Themixture was then cooled to rt. The dioxane was removed. The residue wasdissolved in EtOAc (100 mL), washed with HCl (1N, 30 mL), water (50mL×2), and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated.The residue was purified via flash chromatography on silica gel using1:2 hexane:ethylacetate to give the desired product (0.41 g, 80% yield).LRMS (ES₊): 507.1 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.68–7.65 (m, 1H), 7.50–7.45(m, 1H), 7.36–7.16 (m, 5H), 4.16 (t, 2H), 3.64–3.62 (m, 2H), 3.47 (br,3H), 3.17 (t, 2H), 2.62 (t, 2H), 1.98–1.96 (m, 3H).

Example 41-[3-(aminomethyl)-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one

Part A.1-(3-chloro-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one(0.35 g, 0.69 mmol), Zn(CN)₂ (81 mg, 0.69 mmol), Pd₂(dba)₃ (63 mg, 0.07mmol), dppf (77 mg, 0.14 mmol), and Zn (9 mg, 0.14 mmol) were added to15 mL of DMAC. The mixture was degassed under argon and stirred at 140°C. under N₂ for 12 h. The reaction was cooled to rt, ethylacetate (75mL) was added and the mixture was filtered through Celite®. The filtratewas washed with saturated NaHCO₃ solution (30 mL), water (30 mL×3), andbrine (20 mL). It was then dried over Na₂SO₄, filtered, andconcentrated. The residue was purified via flash chromatography onsilica gel with 10% methanol in dichloromethane to give2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile(0.17 g, 50% yield). LRMS (AP⁺): 498.2 (M+H)⁺. ¹H NMR (CDCl₃) δ7.91–7.85 (m, 2H), 7.31 (s, 4H), 7.28–7.25 (m, 1H), 4.16 (t, 2H),3.63–3.61 (m, 2H), 3.18 (t, 2H), 2.56 (t, 2H), 1.96–1.93 (m, 4H).

Part B. The product from part A (50 mg) was dissolved in 20 mL of MeOHin a hydrogenation bottle. To the solution was added 5% Pd/C (20 mg) andone drop of TFA. The reaction mixture was put on hydrogenation Parrshaker at rt under 50 psi for 5 h. The reaction mixture was filteredthrough Celite®. The filtrate was concentrated and purified via HPLC(C18 RP., 0.5% TFA, H2O/MeCN gradient) to give 40 mg of the titlecompound as its TFA salt(65%). LRMS (ESI+): 502.4 (M+H)+. 1H NMR (CDCl3)δ 7.61 (s, 1H), 7.52 (d, 1H), 7.38 (d, 2H), 7.25 (d, 2H), 7.16–7.09 (m,1H), 4.13 (t, 2H), 3.76 (s, 2H), 3.58 (br, 2H), 3.14 (t, 2H), 2.48 (br,2H), 1.93 (br, 4H).

Example 51-(3-amino-1,2-benzisoxazol-5-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one

Acetohydroxamic acid (54 mg, 0.72 mmol) and K₂CO₃ (0.2 g, 1.45 mmol)were added to 8 mL of DMF and 4 mL of H₂O. The mixture was stirred at rtfor 15 min, followed by addition of a solution of2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile(0.12 g, 0.24 mmol) in DMF(2 mL). The mixture was stirred at rtovernight. The mixture was then partitioned between ethylacetate (40 mL)and water (20 mL), washed with H₂O (20 mL×3) and brine (20 mL), driedover Na₂SO₄, filtered, and concentrated. HPLC (C18 RP., 0.5% TFA,H₂O/MeCN gradient) purification gave 100 mg (67% yield) of the titlecompound as its TFA salt. LRMS (ESI⁻): 623.4 (M+TFA−H)⁻. ¹H NMR (CDCl₃)δ 7.80 (s, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.34–7.24 (m, 4H), 4.16 (t,2H), 3.98 (br, 2H), 3.61 (br, 2H), 3.20 (t, 2H), 2.60 (br, 2H),1.98–1.89 (m, 4H).

Example 61-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL,470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C.5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL)was added dropwise to the reaction. The reaction was warmed to rt andstirred overnight. Reaction was cooled to 0° C. and potassiumtert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction waswarmed to rt and stirred overnight. The reaction was concentrated andthen redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL),extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL),washed with brine (1×250 mL), and dried (Na₂SO₄). Purification by silicagel chromatography using 0%–100% ethyl acetate/hexane gradient as eluentto afford 51.03 g (81%): ¹H NMR (CDCl₃) δ 7.70 (d,j=8.4 Hz, 2H), 7.03(d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H),2.50–1.88 (m, 4H) ppm.

Part B. The product from part A (85.17 g, 282.8 mmol) and phosphoruspentachloride (205.91 g, 990.0 mmol) was dissolved into CHCl₃ (750 mL)and refluxed for 3½ h. Reaction was poured over ice and then quenchedfurther with water, extracted with CHCl₃ (3×400 mL), washed with brine(1×400 mL), dried (MgSO₄), and concentrated. This residue was dissolvedin morpholine (400 mL) and refluxed overnight. Reaction was concentratedand purified by silica gel chromatography using 0%–100% ethylacetate/hexane gradient as eluent to afford 68 g (63%): ¹H NMR (CDCl₃) δ7.68 (d,j=8.8 Hz, 2H), 7.11 (d,j=8.8 Hz, 2H), 5.66 (t,j=4.8 Hz, 1H),3.82 (t,j=4.8 Hz, 4H), 3.77 (t,j=6.8 Hz, 2H), 2.89 (t,j=4.8 Hz, 4H),2.53–2.47 (m, 2H) ppm.

Part C. 4-Dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved intoCH₂Cl₂ (130 mL) and cooled to 0° C. Trifluoroacetic anhydride (4.54 g,32.01 mmol) was added and the mixture was stirred at 0° C. for 30 min.The above morpholine-enamine from part B (10.25 g, 26.68 mmol) dissolvedin CH₂Cl₂ (370 mL) was added slowly and the reaction was warmed to rtand stirred overnight. Reaction was concentrated and purified by silicagel chromatography using 0%–50% ethyl acetate/hexane gradient to isolatethe intermediate. The intermediate was dissolved in 20% HCl (50 mL) anddiethyl ether (200 mL) and stirred at rt overnight. Reaction wasquenched with water, extracted with ether (3×100 mL), washed with brine(1×100 mL), and dried (Na₂SO₄). The residue was redissolved in petroleumether and the solids filtered. The filtrate was concentrated to afford9.99 g (78%): ¹H NMR (CDCl₃) δ 7.77 (d,j=8.8 Hz, 2H), 7.11 (d,j=8.8 Hz,2H), 3.93 (t,j=6.8 Hz, 2H), 2.92 (t,j=6.8 Hz, 2H) ppm.

Part D. The product from part C (10.0 g, 24.3 mmol) and4-methoxyhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in1N HCl (200 mL) and methanol (400 mL) and refluxed overnight. Thereaction was cooled to rt and quenched with water, extracted with ethylacetate (3×250 mL), washed with brine (1×250 mL), and dried (Na₂SO₄).Purification by silica gel chromatography using 0%–100% ethylacetate/hexane gradient as eluent afforded 9.28 g (74%); ¹H NMR (CDCl₃)δ 7.69 (d,j=9.4 Hz, 2H), 7.45 (d,j=8.8 Hz, 2H), 7.06 (d,j=8.8 Hz, 2H),6.92 (d,j=9.2 Hz, 2H), 4.11 (t,j=6.8 Hz, 2H), 3.81 (s, 3H), 3.15(t,j=6.5 Hz, 2H) ppm; Mass Spec (M+H)⁺ 514.3.

Part E. δ-Valerolactam (0.023 g, 0.214 mmol), cesium carbonate (0.095 g,0.292 mmol), palladium (II) acetate (0.004 g, 0.019 mmol), and9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene (0.015 g, 0.029 mmol)were charged to a flask and flushed with N₂. The above trifluoromethylintermediate (0.100 g, 0.195 mmol) dissolved in 1,4-dioxane (2 mL) wasadded via syringe and the flask was flushed with N₂. The reaction washeated at 100° C. overnight. The reaction was cooled to rt and dilutedwith ethyl acetate (25 mL) and water (25 mL), extracted with ethylacetate (3×25 mL), washed with brine (1×25 mL), and dried (Na₂SO₄).Purification by HPLC and freeze-drying afforded 32.4 mg (34%); ¹H NMR(CDCl₃) δ 7.46 (d,j=8.8 Hz, 2H), 7.35 (d,j=7.9 Hz, 2H), 7.24 (d,j=8.7Hz, 2H), 6.93 (d,j=9.1 Hz, 2H), 4.15 (t,j=6.8 Hz, 2H), 3.82 (s, 3H),3.63–3.60 (m, 2H), 3.17 (t,j=6.6 Hz, 2H), 2.64 (t,j=5.7 Hz, 2H),1.98–1.94 (m, 4H) ppm; Mass Spec (M+H)⁺ 485.5.

Example 71-(4-methoxyphenyl)-6-[4-(2-oxohexahydro-1H-azepin-1-yl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was synthesized following the procedure for Example6. ¹H NMR (CDCl₃) δ 7.46 (d,j=9.2 Hz, 2H), 7.32 (d,j=8.5 Hz, 2H), 7.21(d,j=8.8 Hz, 2H), 6.92 (d,j=9.1 Hz, 2H), 4.14 (t,j=6.6 Hz, 2H), 3.81 (s,3H), 3.76–3.72 (m, 2H), 3.16 (t,j=6.6 Hz, 2H), 2.74–2.72 (m, 2H),190–1.78 (m, 6H) ppm; Mass Spec (M+H)⁺ 499.4.

Example 81-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperazinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL,470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C.5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL)was added dropwise to the reaction. The reaction was warmed to rt andstirred overnight. Reaction was cooled to 0° C. and potassiumtert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction waswarmed to rt and stirred overnight. The reaction was concentrated andthen redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL),extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL),washed with brine (1×250 mL), and dried (Na₂SO₄). Purification by silicagel chromatography using 0%–100% ethyl acetate/hexane gradient as eluentto afford 51.03 g (81%): ¹H NMR (CDCl₃) δ 7.70 (d,j=8.4 Hz, 2H), 7.03(d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H),2.50–1.88 (m, 4H) ppm.

Part B. The product from part A (85.17 g, 282.8 mmol) and phosphoruspentachloride (205.91 g, 990.0 mmol) was dissolved into CHCl₃ (750 mL)and refluxed for 3½ h. Reaction was poured over ice and then quenchedfurther with water, extracted with CHCl₃ (3×400 mL), washed with brine(1×400 mL), dried (MgSO₄), and concentrated. This residue was dissolvedin morpholine (400 mL) and refluxed overnight. Reaction was concentratedand purified by silica gel chromatography using 0%–100% ethylacetate/hexane gradient as eluent to afford 68 g (63%): ¹H NMR (CDCl₃) δ7.68 (d,j=8.8 Hz, 2H), 7.11 (d,j=8.8 Hz, 2H), 5.66 (t,j=4.8 Hz, 1H),3.82 (t,j=4.8 Hz, 4H), 3.77 (t,j=6.8 Hz, 2H), 2.89 (t,j=4.8 Hz, 4H),2.53–2.47 (m, 2H) ppm.

Part C. 4-Dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved intoCH₂Cl₂ (130 mL) and cooled to 0° C. Trifluoroacetic anhydride (4.54 g,32.01 mmol) was added and the mixture was stirred at 0° C. for 30 min.The above morpholine-enamine product from part B (10.25 g, 26.68 mmol)dissolved in CH₂Cl₂ (370 mL) was added slowly and the reaction waswarmed to rt and stirred overnight. Reaction was concentrated andpurified by silica gel chromatography using 0%–50% ethyl acetate/hexanegradient to isolate the intermediate. The intermediate was dissolved in20% HCl (50 mL) and diethyl ether (200 mL) and stirred at rt overnight.Reaction was quenched with water, extracted with ether (3×100 mL),washed with brine (1×100 mL), and dried (Na₂SO₄). The residue wasredissolved in petroleum ether and the solids filtered. The filtrate wasconcentrated to afford 9.99 g (78%): ¹H NMR (CDCl₃) δ 7.77 (d,j=8.8 Hz,2H), 7.11 (d,j=8.8 Hz, 2H), 3.93 (t,j=6.8 Hz, 2H), 2.92 (t,j=6.8 Hz, 2H)ppm.

Part D. The product from part C (10.0 g, 24.3 mmol) and4-methoxyhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in1N HCl (200 mL) and methanol (400 mL) and refluxed overnight. Thereaction was cooled to rt and quenched with water, extracted with ethylacetate (3×250 mL), washed with brine (1×250 mL), and dried (Na₂SO₄).Purification by silica gel chromatography using 0%–100% ethylacetate/hexane gradient as eluent afforded 9.28 g (74%); ¹H NMR (CDCl₃)δ 7.69 (d,j=9.4 Hz, 2H), 7.45 (d,j=8.8 Hz, 2H), 7.06 (d,j=8.8 Hz, 2H),6.92 (d,j=9.2 Hz, 2H), 4.11 (t,j=6.8 Hz, 2H), 3.81 (s, 3H), 3.15(t,j=6.5 Hz, 2H) ppm; Mass Spec (M+H)⁺ 514.3.

Part E. 4-Benzyloxycarbonylpiperazin-2-one (0.050.214 mmol), cesiumcarbonate (0.095 g, 0.292 mmol), palladium (II) acetate (0.004 g, 0.019mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.015 g,0.029 mmol) were charged to a flask and flushed with N₂. The abovetrifluoromethyl intermediate (0.100 g, 0.195 mmol) dissolved in1,4-dioxane (2 mL) was added via syringe and the flask was flushed withN₂. The reaction was heated at 100° C. overnight. The reaction wascooled to rt and diluted with ethyl acetate (25 mL) and water (25 mL),extracted with ethyl acetate (3×25 mL), washed with brine (1×25 mL), anddried (Na₂SO₄). The lactam (0.091 g, 0.146 mmol) was dissolved in 6N HCl(20 mL) and MeOH (5 mL) and refluxed for 2 h. Reaction was quenched withwater (20 mL) and washed with ether (3×20 mL), basified to pH 12 with 1NNaOH, extracted again with ether (3×20 mL), washed with brine (1×20 mL),and dried (Na₂SO₄). Purification by HPLC and freeze-drying to afford 1mg (1% overall); ¹H NMR (CDCl₃) δ 7.37 (d,j=9.0 Hz, 2H), 7.328d,j=8.3Hz, 2H), 7.24–7.18 (m, 2H), 6.84 (d,j=8.8 Hz, 2H), 4.05 (t,j=6.6 Hz,2H), 3.79–3.60 (m, 5H), 3.73 (s, 3H), 3.32(bs, 2H), 3.16 (t,j=6.5 Hz,2H) ppm; Mass Spec (M+H)⁺ 486.4.

Example 91-(4-methoxyphenyl)-6-[4-(2-oxo-1-imidazolidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To the trifluoromethyl intermediate prepared previously (part D, example6, 0.120 g, 0.234 mmol), 2-imidazolidone (0.025 g, 0.281 mmol),potassium carbonate (0.081 g, 0.257 mmol), 1,10-phenanthraline (0.006 g,0.012 mmol) and DMSO (6 mL) were charged to a flask and degassed for 15min. Copper (I) iodide (0.007 g, 0.012 mmol) was added and the reactionwas heated to 130° C. overnight. The reaction was cooled to rt andquenched with H₂O (20 mL) and ethyl acetate (20 mL), washed with H₂O(3×20 mL), washed with brine (1×30 mL), and dried (Na₂SO₄). Purificationby HPLC and freeze-drying afforded 29.1 mg (26%); ¹H NMR (CDCl₃) δ7.53–7.45 (m, 4H), 7.28 (d,j=11.0 Hz, 2H), 6.92 (d,j=9.1 Hz, 2H), 4.12(t,j=6.8 Hz, 2H), 3.96 (t,j=8.1 Hz, 2H), 3.81 (s, 3H), 3.63 (t,j=8.2 Hz,2H), 3.16 (t,j=6.6 Hz, 2H) ppm; Mass Spec (M+H)⁺ 472.5.

Example 101-(4-methoxyphenyl)-6-[4-(2-oxotetrahydro-1(2H)-pyrimidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was synthesized following the procedure for Example6. ¹H NMR (CDCl₃) δ 7.46 (d,j=8.8 Hz, 4H), 7.34–7.24 (m, 2H), 6.93(d,j=9.1 Hz, 2H), 4.15 (t,j=6.8 Hz, 2H), 3.82 (s, 3H), 3.68 (t,j=5.7 Hz,2H), 3.63 (t,j=5.7 Hz, 2H), 3.17 (t,j=6.4 Hz, 2H), 2.18–2.09 (m, 2H)ppm; Mass Spec (M+H)⁺ 486.5.

Example 116-[4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was synthesized following the procedure for Example6. ¹H NMR (CDCl₃) δ 7.58–7.47 (m, 5H), 7.28 (d,j=7.3 Hz, 1H), 7.16–7.08(m, 1H), 7.04–6.98 (m, 4H), 6.52 (t,j=2.4 Hz, 1H), 4.14 (t,j=6.6 Hz,2H), 3.91(q, j=7.6 Hz, 2H), 3.78 (s, 3H), 3.18 (t,j=6.6 Hz, 2H), 1.23(t,j=7.2 Hz, 3H) ppm; Mass Spec (M+H)⁺ 548.5.

Example 121-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile

Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL,470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C.5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL)was added dropwise to the reaction. The reaction was warmed to rt andstirred overnight. Reaction was cooled to 0° C. and potassiumtert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction waswarmed to rt and stirred overnight. The reaction was concentrated andthen redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL),extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL),washed with brine (1×250 mL), and dried (Na₂SO₄). Purification by silicagel chromatography using 0%–100% ethyl acetate/hexane gradient as eluentto afford 51.03 g (81%): ¹H NMR (CDCl₃) δ 7.70 (d,j=8.4 Hz, 2H), 7.03(d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H),2.50–1.88 (m, 4H) ppm.

Part B. The product from part A (85.17 g, 282.8 mmol) and phosphoruspentachloride (205.91 g, 990.0 mmol) was dissolved into CHCl₃ (750 mL)and refluxed for 3½ h. Reaction was poured over ice and then quenchedfurther with water, extracted with CHCl₃ (3×400 mL), washed with brine(1×400 mL), dried (MgSO₄), and concentrated. This residue was dissolvedin morpholine (400 mL) and refluxed overnight. Reaction was concentratedand purified by silica gel chromatography using 0%–100% ethylacetate/hexane gradient as eluent to afford 68 g (63%): ¹H NMR (CDCl₃) δ7.68 (d,j=8.8 Hz, 2H), 7.11 (d,j=8.8 Hz, 2H), 5.66 (t,j=4.8 Hz, 1H),3.82 (t,j=4.8 Hz, 4H), 3.77 (t,j=6.8 Hz, 2H), 2.89 (t,j=4.8 Hz, 4H),2.53–2.47 (m, 2H) ppm.

Part C. To p-anisidine (16 g, 0.129 mol) in conc. HCl (40 mL), 100 mLH₂O, cooled to −5° C. and sodium nitrite (9.4 g, 0.136 mol) in H₂O (60mL) was added. The diazotization was stirred cold for 20 min and amixture of ethylchloroacetoacetate (22 g, 0.133 mol), ethanol (100 mL),sodium acetate (32 g, 0.389 mol) and H₂O (400 mL) was added. Thereaction was allowed to warm to rt and stirred for 2 h. The productprecipitated as a black solid (30 g) that was collected and dried invacuo. ¹H NMR (CDCl₃) δ 8.28 (s, 1H), 7.18 (d,j=9.1 Hz, 2H), 6.90(d,j=9.2 Hz, 2H), 4.41(q, j=7 Hz, 2H), 3.80 (s, 3H), 1.42 (t,j=7.3 Hz,3H) ppm.

Part D. Crude chloro ester hydrazone from Part C (30 g, 0.117 mol),iodo-morpholine enamine from example 6 (29.9 g, 0.078 mol), andtriethylamine (74 mL, 0.53 mol) were heated to reflux in toluene (400mL) for 24 h. The reaction was cooled, washed with water, dried(Na₂SO₄). Purification by silica gel chromatography using 1:1hexane/ethyl acetate as eluent afforded the morpholine intermediate.Treatment of the morpholine intermediate with trifluoroacetic acid (50mL) in CH₂Cl₂ (500 mL) for 24 h followed by washing with water anddrying (Na₂SO₄) afforded 28.8 g (71%) of the ester/iodo; Mass Spec(M+H)⁺ 517.9.

Part E. To ammonium chloride (1 g, 19 mmol) in xylenes (250 mL) wasadded trimethyl aluminum (2M heptanes, 19.3 mL, 38 mmol) and stirred for20 min. The above ester from part D (9.1 g, 17.6 mmol) was added and thereaction was heated to reflux for 3 h. The reaction was cooled to 0° C.,quenched with HCl and extracted with ethyl acetate; washed with brineand dried (Na₂SO₄). The amide/nitrile mixture obtained was treated with30% H₂O₂ (70 mL), 10% NaOH (150 mL) in CH₂Cl₂ (400 mL) for 24 h.Extraction of the aqueous layer with CH₂Cl₂; washing with water anddrying (Na₂SO₄) afforded 6.18 g of the amide (72%); ¹H NMR (CDCl₃) δ7.68 (d,j=8.5 Hz, 2H), 7.47 (d,j=8.8 Hz, 2H), 7.09 (d,j=8.8 Hz, 2H),6.95 (d,j=8.8 Hz, 2H), 6.86 (s, 1H), 5.70 (s, 1H), 4.10 (t,j=6.6 Hz,2H), 3.82 (s, 3H), 3.17 (t,j=6.6, 2H) ppm.

Part F. To DMF (4.28 mL, 55.3 mmol) dissolved in 150 mL acetonitrile at0° C. was added oxalyl chloride (3.99 mL, 46.1 mmol) and stirred untilall of gas evolution had stopped. The above amide from part E (9.0 g,18.4 mmol) was added and stirred until a homogenous mixture had formed.Pyridine (7.45 mL, 92.2 mmol) was added and the reaction was warmed tort and stirred for 2 h. The reaction was quenched with 1N HCl, extractedwith ether, washed with brine and dried (Na₂SO₄) to afford 6.54 g (75%)of the nitrile; ¹H NMR (CDCl₃) δ 7.70 (d,j=8.8 Hz, 2H), 7.45 (d,j=9.2Hz, 2H), 7.05 (d,j=8.8 Hz, 2H), 6.92 (d,j=8.8 Hz, 2H), 4.13 (t,j=6.6 Hz,2H), 3.83 (s, 3H), 3.17 (t,j=6.6 Hz, 2H) ppm; Mass Spec (M+H)⁺ 470.9.

Part G. δ-Valerolactam (0.127 g, 1.276 mmol), cesium carbonate (0.520 g,1.595 mmol), palladium (II) acetate (0.024 g, 0.106 mmol), and9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene (0.092 g, 0.159 mmol)were charged to a flask and flushed with N₂. The above trifluoromethylintermediate from part F (0.500 g, 1.063 mmol) dissolved in 1,4-dioxane(10 mL) was added via syringe and the flask was flushed with N₂. Thereaction was heated at 100° C. overnight. The reaction was cooled to rtand diluted with ethyl acetate (25 mL) and water (25 mL), extracted withethyl acetate (3×25 mL), washed with brine (1×25 mL), and dried(Na₂SO₄). Purification by HPLC and freeze-drying afforded 104.2 mg(22%); ¹H NMR (CDCl₃) δ 7.46 (d,j=8.8 Hz, 2H), 7.34–7.25 (m, 4H), 6.93(d,j=9.2 Hz, 2H), 4.15 (t,j=6.6 Hz, 2H), 3.82 (s, 3H), 3.64–3.56 (m,2H), 3.17 (t,j=6.6 Hz, 2H), 2.60–2.52 (m, 2H), 1.98–1.90 (m, 4H) ppm;Mass Spec (M+H)⁺ 442.3.

Example 131-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(1H-tetraazol-5-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL,470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C.5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL)was added dropwise to the reaction. The reaction was warmed to rt andstirred overnight. Reaction was cooled to 0° C. and potassiumtert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction waswarmed to rt and stirred overnight. The reaction was concentrated andthen redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL),extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL),washed with brine (1×250 mL), and dried (Na₂SO₄). Purification by silicagel chromatography using 0%–100% ethyl acetate/hexane gradient as eluentto afford 51.03 g (81%): ¹H NMR (CDCl₃) δ 7.70 (d,j=8.4 Hz, 2H), 7.03(d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H),2.50–1.88 (m, 4H) ppm.

Part B. The above lactam intermediate from part A (85.17 g, 282.8 mmol)and phosphorus pentachloride (205.91 g, 990.0 mmol) was dissolved intoCHCl₃ (750 mL) and refluxed for 3½ h. Reaction was poured over ice andthen quenched further with water, extracted with CHCl₃ (3×400 mL),washed with brine (1×400 mL), dried (MgSO₄), and concentrated. Thisresidue was dissolved in morpholine (400 mL) and refluxed overnight.Reaction was concentrated and purified by silica gel chromatographyusing 0%–100% ethyl acetate/hexane gradient as eluent to afford 68 g(63%): ¹H NMR (CDCl₃) δ 7.68 (d,j=8.8 Hz, 2H), 7.11 (d,j=8.8 Hz, 2H),5.66 (t,j=4.8 Hz, 1H), 3.82 (t,j=4.8 Hz, 4H), 3.77 (t,j=6.8 Hz, 2H),2.89 (t,j=4.8 Hz, 4H), 2.53–2.47 (m, 2H) ppm.

Part C. To p-anisidine (16 g, 0.129 mol) in conc. HCl (40 mL), 100 mLH₂O, cooled to −5° C. and sodium nitrite (9.4 g, 0.136 mol) in H₂O (60mL) was added. The diazotization was stirred cold for 20 min and amixture of ethylchloroacetoacetate (22 g, 0.133 mol), ethanol (100 mL),sodium acetate (32 g, 0.389 mol) and H₂O (400 mL) was added. Thereaction was allowed to warm to rt and stirred for 2 h. The productprecipitated as a black solid (30 g) which was collected and dried invacuo. ¹H NMR (CDCl₃) δ 8.28 (s, 1H), 7.18 (d,j=9.1 Hz, 2H), 6.90 (d,j=9.2 Hz, 2H), 4.41(q, j=7 Hz, 2H), 3.80 (s, 3H), 1.42 (t,j=7.3 Hz, 3H)ppm.

Part D. Crude chloro ester hydrazone from Part C (30 g, 0.117 mol),iodo-morpholine from Part B (29.9 g, 0.078 mol), and triethylamine (74mL, 0.53 mol) were heated to reflux in toluene (400 mL) for 24 h. Thereaction was cooled, washed with water, dried (Na₂SO₄). Purification bysilica gel chromatography using 1:1 hexane/ethyl acetate as eluentafforded the morpholine intermediate. Treatment of the morpholineintermediate with trifluoroacetic acid (50 mL) in CH₂Cl₂ (500 mL) for 24h followed by washing with water and drying (Na₂SO₄) afforded 28.8 g(71%) of the ester/iodo; Mass Spec (M+H)⁺ 517.9.

Part E. To ammonium chloride (1 g, 19 mmol) in xylenes (250 mL) wasadded trimethyl aluminum (2M heptanes, 19.3 mL, 38 mmol) and stirred for20 min. The above ester (9.1 g, 17.6 mmol) was added and the reactionwas heated to reflux for 3 h. The reaction was cooled to 0° C., quenchedwith HCl and extracted with ethyl acetate; washed with brine and dried(Na₂SO₄). The amide/nitrile mixture obtained was treated with 30% H₂O₂(70 mL), 10% NaOH(150 mL) in CH₂Cl₂ (400 mL) for 24 h. Extraction of theaqueous layer with CH₂Cl₂; washing with water and drying (Na₂SO₄)afforded 6.18 g of the amide (72%); ¹H NMR (CDCl₃) δ 7.68 (d,j=8.5 Hz,2H), 7.47 (d,j=8.8 Hz, 2H), 7.09 (d,j=8.8 Hz, 2H), 6.95 (d,j=8.8 Hz,2H), 6.86 (s, 1H), 5.70 (s, 1H), 4.10 (t,j=6.6 Hz, 2H), 3.82 (s, 3H),3.17 (t,j=6.6, 2H) ppm.

Part F. To DMF (4.28 mL, 55.3 mmol) dissolved in 150 mL acetonitrile at0° C. was added oxalyl chloride (3.99 mL, 46.1 mmol) and stirred untilall of gas evolution had stopped. The above amide (9.0 g, 18.4 mmol) wasadded and stirred until a homogenous mixture had formed. Pyridine (7.45mL, 92.2 mmol) was added and the reaction was warmed to rt and stirredfor 2 h. The reaction was quenched with 1N HCl, extracted with ether,washed with brine and dried (Na₂SO₄) to afford 6.54 g (75%) of thenitrile; ¹H NMR (CDCl₃) δ 7.70 (d,j=8.8 Hz, 2H), 7.45 (d,j=9.2 Hz, 2H),7.05 (d,j=8.8 Hz, 2H), 6.92 (d,j=8.8 Hz, 2H), 4.13 (t,j=6.6 Hz, 2H),3.83 (s, 3H), 3.17 (t,j=6.6 Hz, 2H) ppm; Mass Spec (M+H)⁺ 470.9.

Part G. Tributyl tin chloride (0.142 g, 1.06 mmol) was added dropwise toa solution of sodium azide (0.553 g, 8.51 mmol) in THF (2 mL) at 0° C.The above nitrile (0.500 g, 1.06 mmol) was added and the reaction wasrefluxed overnight. The reaction was cooled to rt and slowly quenchedwith 6N HCl (4 mL), diluted with H₂O (20 mL) and ethyl acetate (20 mL),extracted with ethyl acetate (3×20 mL), washed with brine (1×25 mL), anddried (Na₂SO₄) to afford 455 mg (83%); ¹H NMR (CDCl₃) δ 7.69 (d,j=8.4Hz, 2H), 7.44 (d,j=8.7 Hz, 2H), 7.18) d,j=7.7 Hz, 1H), 7.08 (d,j=8.4 Hz,2H), 6.92 (d,j=8.8 Hz, 2H), 4.14 (t,j=6.6 Hz, 2H), 3.82 (s, 3H), 3.48(t,j=6.4 Hz, 2H) ppm; Mass Spec (M+H)⁺ 514.0.

Part H. Triphenylmethyl chloride (0.230 g, 0.826 mmol) and 10N NaOH(0.10 mL, 0.991 mmol) were added to the above tetrazole (0.424 g, 0.826mmol) dissolved in toluene (10 mL) and stirred at rt overnight. Thereaction was quenched with water (50 mL), extracted with ethyl acetate(3×75 mL), washed with brine (1×50 mL) and dried (Na₂SO₄) afforded theprotected tetrazole intermediate. δ-Valerolactam (0.106 g, 1.07 mol),cesium carbonate (0.437 g, 1.34 mmol), palladium (II) acetate (0.020 g,0.089 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.123g, 0.134 mmol) were charged to a flask and flushed with N₂. Theprotected tetrazole/iodo intermediate (0.676 g, 0.895 mmol) dissolved in1,4-dioxane (10 mL) was added via syringe and the flask was flushed withN₂. The reaction was heated at 60° C. overnight. The reaction was cooledto rt and diluted with ethyl acetate (75 mL) and water (75 mL),extracted with ethyl acetate (3×100 mL), washed with brine (1×75 mL),and dried (Na₂SO₄). Purification by silica gel chromatography using0%–100% ethyl acetate/hexane gradient as eluent afforded the protectedtetrazole/lactam intermediate. The protected tetrazole/lactamintermediate (0.249 g, 0.322 mmol), trifluoroacetic acid (5 mL), water(5 mL) and THF (30 mL) were charged to a flask and stirred at rt for 2h. Additional trifluoroacetic acid (20 mL) and water (20 mL) was addedand the reaction was stirred overnight at rt. The reaction was basifiedto pH 10 with 10N NaOH and washed with CH₂Cl₂ (3×75 mL). The aqueouslayer was acidified to pH 3 with 1N HCl, extracted with ethyl acetate(3×75 mL), washed with brine (1×50 mL), and dried (MgSO₄). Purificationby HPLC and freeze-drying afforded 13.4 mg (4% overall); ¹H NMR (CD₃OD)δ 7.54 (d,j=8.8 Hz, 3H), 7.43 (d,j=8.8 Hz, 2H), 7.32 (d,j=8.8 Hz, 2H),7.00 (d,j=9.2 Hz, 2H), 4.20 (t,j=6.8 Hz, 2H), 3.84 (s, 3H), 3.67(t,j=5.3 Hz, 2H), 3.42 (t,j=6.6 Hz, 2H), 2.51 (t,j=6.1 Hz, 2H),1.98–1.94 (m, 4H) ppm; Mass Spec (M+H)⁺ 485.3.

Example 141-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxo-1-piperidinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide

Part A. A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solutionwas cooled to −78° C. and 2-acetylfuran (14 g, 12 m mmol) was added inone portion. After 5 min, di-tert-butyl oxalate was added dropwise over1 h as a solution in 100 mL of ether. The resulting mixture was warmedto 23° C. over a period of 3 h and was maintained at rt for 20 h. Themixture was then filtered, and the resulting beige precipitate waswashed with 100 mL of ether. The filter cake was then dried in a vacuumoven for 1 h to afford lithium1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (25 g, 83%) as acream colored solid. ¹H NMR (DMSO-d₆) δ 7.75 (t, 1H), 6.96 (m, 1H), 6.56(m, 1H), 3.34 (s, 2H), 1.46 (s, 9H).

Part B. To the product (13 g, 54 mmol) from Part A was added2-fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250mL of acetic acid. The resulting orange mixture was maintained at rt for20 h and then concentrated to dryness. The resulting residue was takenup in 30% CHCl₃ in hexanes and filtered to afford tert-butyl1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate (18 g,95%) as a light brown solid. LC/MS (ESI⁺): 354.2 (M+H)⁺. ¹H NMR (CDCl₃)δ 7.64–7.78 (m, 3H), 7.42 (s, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 6.30 (s,1H), 1.61 (s, 9H).

Part C. To the product from Part B (10 g, 28 mmol) was added 125 mL ofCH₂Cl₂ and 125 mL of trifluoroacetic acid. The resulting black solutionwas maintained at rt under N₂ for 2 h and was then concentrated todryness. The resulting solid was dried in a vacuum oven for 4 h toafford 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate(8.4 g, 99%) as a brown solid. LC/MS (ESI⁺): 298.1 (M+H)⁺. ¹H NMR(CD₃OD) δ 7.90 (m, 1H), 7.75 (m, 1H), 7.51 (s, 1H), 7.46 (t, 1H), 6.98(s, 1H), 6.47 (m, 1H), 6.35 (m, 1H).

Part D. To the product (4.1 g, 14 mmol) from Part C was added 23 mL ofCH₂Cl₂ and 2.0 M oxalyl chloride (10 mL, 21 mmol) in CH₂Cl₂. Upondropwise addition of DMF (10 drops) to the brown mixture, all solidsdissolved over a period of 30 min. When no more gas evolved, the brownsolution was concentrated. The resulting residue was redissolved in 100mL of CH₂Cl₂ and 0.5 M ammonia in dioxane (110 mL, 55 mmol) was addedvia cannula. After 30 min, the resulting suspension was concentrated andpoured into H₂O. The aqueous layer was washed with ethyl acetate (3×70mL), and the combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The resulting residue was dissolvedin 10 mL of CH₂Cl₂ and 50 mL of hexanes were added. The resultingsuspension was filtered, and the filter cake was washed with 50 mL ofhexanes. The filter cake was dried in a vacuum oven to afford1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxamide (2.5 g,62%) as a brown solid. LC/MS (ESI⁺): 297.1 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.75(m, 1H), 7.64 (m, 1H), 7.42 (s, 1H), 7.33 (t, 1H), 7.16 (s, 1H), 6.79(br s, 1H), 6.46 (m, 1H), 6.36 (m, 1H), 5.50 (br s, 1H).

Part E. To the product (2.5 g, 8.3 mmol) from Part D was added H₂O (51mL), 5% aqueous NaH₂PO₄ (35 mL), and tert-butanol (51 mL). The resultingmixture was warmed to 60° C., and KMnO₄ (8.0 g, 51 mmol) was added overa period of 10 min. After an additional 10 min, the resulting purpleslurry was cooled to 0° C., and the reaction was quenched by theaddition of 200 mL of saturated aqueous sodium bisulfite. The resultingmixture was filtered, washed with 300 mL of H₂O, and the filtrate wasacidified with conc. HCl. The aqueous layer was extracted with EtOAc(6×100 mL) and the combined organic layers were washed with brine, driedover Na₂SO₄, and filtered. Concentration afforded3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylicacid (1.6 g, 71%) as a yellow solid. LC/MS (ESI⁺): 275.1 (M+H)⁺. ¹H NMR(CD₃OD) δ 8.03 (m, 1H), 7.90 (m, 1H), 7.5 (t, 1H), 7.44 (s, 1H).

Part F. 5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate(3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mLof THF. The solution was stirred for 12 h at rt under N₂ and was thenconcentrated. The residue was taken up in EtOAc and the mixture wasfiltered. The filtered solid was washed with 100 mL of hexanes and driedto give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid(3.1 g, 78%). LRMS (AP⁺): 304.2 (M+H+ACN)⁺. ¹H NMR (CDCl₃) δ 8.51 (d,1H), 8.23–8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H).

Part G. The product from Part F (1.0 g, 4.3 mmol) was dissolved in 100mL of MeOH. Palladium hydroxide, 20 wt % Pd, Degussa type (100 mg), wasadded, and the resulting mixture was subjected to a hydrogen atmosphere(50 psi) and shaken vigorously. After 5 h, the black mixture wasfiltered and concentrated to affordtert-butyl-5-amino-1-indolinecarboxylate as a brown oil (0.98 g, 98%).LRMS (ESI⁺): 235.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 6.88 (br m, 3H), 3.96 (m,2H), 3.04 (m, 2H), 1.55 (br s, 9H).

Part H. To tert-butyl-5-amino-1-indolinecarboxylate (1.90 g, 8.2 mmol)was added 5-bromovaleryl chloride (1.4 mL, 9.0 mmol) and 18 mL of THF.After stirring for 5 min at rt under N₂, potassium tert-butoxide (9 mL,9 mmol; 1.0 M in THF) was added in one portion, and the resulting brownsolution was stirred under N₂ for 30 min. A second portion of potassiumtert-butoxide (9 mL) was added, and the resulting brown suspension wasstirred for 15 min. An additional 0.10 mL-portion of 5-bromovalerylchloride and a 4.5 mL-portion of potassium tert-butoxide were added, andthe mixture was stirred for 30 min. The reaction was then poured intoH₂O (80 mL). The aqueous layer was washed with EtOAc (3×50 mL), and thecombined organic layers were washed with brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated and the resulting residue waspurified by radial chromatography (50% EtOAc in hexanes) to affordtert-butyl 5-(2-oxo-1-piperidinyl)-1-indolinecarboxylate as a pink solid(1.30 g, 50%). LRMS (AP⁺): 317.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.40–7.80 (brm, 1H), 7.01 (s, 1H), 6.97 (d, 1H), 3.94 (t, 2H), 3.55 (br m, 2H), 3.09(t, 2H), 2.49 (br m, 2H), 1.91 (br m, 4 H), 1.52 (s, 9H).

Part I. The product from Part H (1.30 g, 4.2 mmol) was dissolved in 30mL of CH₂Cl₂ and stirred at rt under N₂. Trifluoroacetic acid (30 mL)was added, and the reaction was stirred for 2 h. The yellow solution wasconcentrated, and the resulting residue was dissolved in EtOAc (50 mL)and washed with saturated aqueous NaHCO₃. The aqueous layer was washedwith EtOAc (2×50 mL) and the combined organic layers were dried overNa₂SO₄ and concentrated to afford1-(2,3-dihydro-1H-indol-5-yl)-2-piperidinone (740 mg, 81%) as a beigesolid (LC/MS (ESI⁺): 217.2 (M+H)⁺). To this solid was added3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylicacid (1.00 g, 3.8 mmol)(see Part E above), followed by 28 mL of pyridineand 6.8 mL of DMF. 1,3-Diisopropyl-carbodiimide (0.59 mL, 3.8 mmol) wasadded, and the resulting solution was stirred for 14 h. The reaction wasthen poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3×50 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,and filtered. Concentration of the filtrate afforded crude1-(3-cyano-4-fluorophenyl)-5-{[5-(2-oxo-1-piperidinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide(1.20 g; LC/MS (ESI⁺): 473.2 (M+H)⁺) as a brown residue. This residuewas dissolved in 18 mL of DMF and 3 mL of H₂O. Potassium carbonate (1.70g, 13 mmol) and acetohydroxamic acid (470 mg, 6.2 mmol) were added, andthe resulting mixture was warmed to 50° C. under an N₂ atmosphere. After2 h, the reaction was cooled to rt and poured into EtOAc (60 mL). Theorganic layer was washed with H₂O (2×50 mL), brine, and dried overNa₂SO₄. Filtration and concentration afforded a brown oily residue thatwas purified by preparative LC/MS (C18 reverse phase, eluted with 0.05%TFA in CH₃CN/H₂O) to give the TFA salt of the final product. This saltwas dissolved saturated aqueous NaHCO₃ (15 mL), and the aqueous layerwas washed with EtOAc (3×50 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated to give1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxo-1-piperidinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamideas a white solid (150 mg, 7.3% for 2 steps). LC/MS (ESI⁺): 486.2 (M+H)⁺.¹H NMR (DMSO-d₆) δ 8.08 (s, 1H), 7.91 (d, 1H), 7.85 (s, 1H), 7.67 (m,1H), 7.51–7.57 (br m, 2H), 7.37 (s, 1H), 7.2 (s, 1H), 7.04 (s, 1H), 6.58(s, 2H), 4.28 (br m, 2H), 3.55 (br s, 2H), 3.15 (br m, 2H), 2.36 (br s,2H), 1,82 (br s, 4H).

Example 151-(3-amino-1,2-benzisoxazol-5-yl)-5-{[6-(2-oxo-1-piperidinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamidetrifluoroacetate

The title compound was prepared in the same manner as using6-nitro-1H-indole and following the general procedures describedpreviously. LC/MS (ESI⁺): 486.2 (M+H−TFA)⁺.

Example 161-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide

Part A. To tert-butyl5-(2-oxohexahydro-1H-azepin-1-yl)-1-indolinecarboxylate (140 mg, 0.42mmol) that had been prepared as in Part C of Example 15 using6-bromohexanoyl chloride instead of 5-bromovaleryl chloride was added 10mL of 4.0 M HCl in dioxane. The resulting solution was maintained at rtunder N₂ for 2 h and was then concentrated. The resulting residue wasdissolved in 25 mL of EtOAc, and the organic layer was washed withsaturated aqueous NaHCO₃. The aqueous layer was washed with EtOAc (2×50mL) and the combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated to afford1-(2,3-dihydro-1H-indol-5-yl)hexahydro-2H-azepin-2-one (96 mg, 100%) asa brown oil. LC/MS (ESI⁺): 231.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 6.9 (s, 1H),6.79 (d, 1H), 6.76 (d, 1H), 3.98 (br s, 1H), 3.66 (br m, 2H), 3.52 (t,2H), 3.01 (t, 2H), 2.65 (br s, 2H), 1.78 (br s, 6H).

Part B. To the product from Part A (95 mg, 0.41 mmol), was added3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylicacid (94 mg, 0.34 mmol), 3.3 mL of pyridine, and 0.70 mL of DMF.1,3-Diisopropylcarbodiimide (0.059 mL, 0.38 mmol) was added, and theresulting solution was stirred for 1 h. The red mixture was then pouredinto 1N aqueous HCl (70 mL) and washed with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andfiltered. Concentration of the filtrate and purification of theresulting residue by radial chromatography (1–5% MeOH in CH₂Cl₂) gave1-(3-cyano-4-fluorophenyl)-5-{[5-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-yl]carbonyl}-1H-pyrazole-3-carboxamide(98 mg, 49%) as a brown residue. LC/MS (ESI⁺): 487.1 (M+H)⁺. ¹H NMR(CD₃OD) δ 8.08 (br m, 1H), 7.97 (br d, 1H), 7.87 (br s, 1H), 7.43 (br t,1H), 7.28 (s, 1H), 7.12 (br s, 1H), 7.00 (br d, 1H), 4.24 (br m, 2H),3.73 (br s, 2H), 3.16 (br m, 2H), 2.66 (br s, 2H), 1.79 (br s, 6H).

Part C. To the product from Part B (92 mg, 0.19 mmol) was added 8.8 mLof DMF and 3.4 mL of H₂O. Potassium carbonate (130 g, 0.95 mmol) andacetohydroxamic acid (36 mg, 0.47 mmol) were added, and the resultingmixture was warmed to 50° C. under an N₂ atmosphere. After 2 h, thereaction was cooled to rt and poured into EtOAc (50 mL). The organiclayer was washed with H₂O (2×15 mL), brine, and dried over Na₂SO₄.Filtration and concentration afforded a brown oily residue that waspurified by radial chromatography (10% MeOH in CH₂Cl₂ containing 2%NH₄OH) to yield1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide(11 mg, 12%) as a white solid. LC/MS (ESI⁺): 500.1 (M+H)⁺.

Example 171-(3-amino-1,2-benzisoxazol-5-yl)-5-{[6-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide

Part A. To tert-butyl-6-nitro-1H-indole-1-carboxylate (3.80 g, 14 mmol),prepared according to Part F of Example 14 using 6-nitro-1H-indole asstarting material, was added 150 mL of MeOH and 150 mL of EtOAc. Thesolution was covered with a stream of N₂, and 10 wt % Pd/C (100 mg) wasadded in one portion. The mixture was subjected to a hydrogen atmosphere(50 psi) for 14 h and was then filtered and concentrated. Analysis(LC/MS) of the resulting brown residue (3.34 g, 100%) showed it to be a20:80 mixture of tert-butyl 6-amino-1-indolinecarboxylate:tert-butyl-6-amino-1H-indole-1-carboxylate. LC/MS (ESI⁺): 233.1 (indoleM+H)⁺, 235.1 (indoline M+H)⁺.

Part B. To the mixture from Part A (400 mg, 1.7 mmol) was added6-bromohexanoyl chloride (0.26 mL, 1.7 mmol) and 15 mL of THF. Potassiumtert-butoxide (1.90 mL, 1.9 mmol; 1.0 M in THF) was added and the cloudymixture was stirred for 10 min. A second 1.90-mL portion of potassiumtert-butoxide was added and the reaction was maintained at rt for 1 h.The reaction was then poured into 1N HCl (70 mL), and the aqueous layerwas washed with EtOAc (3×50 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The resultingresidue was purified by radial chromatography to give a mixture oftert-butyl 6-(2-oxohexahydro-1H-azepin-1-yl)-1-indolinecarboxylate andtert-butyl 6-(2-oxohexahydro-1H-azepin-1-yl)-1H-indole-1-carboxylate(340 mg, 60%) as a red oil. LC/MS (ESI⁺): 329.3 (indole M+H)⁺, 331.2(indoline M+H)⁺.

Part C. To the product from Part B was added 5 mL of trifluoroaceticacid and NaBH₃CN (260 mg, 4.1 mmol). After 2 h, an additional 100mg-portion of borohydride was added. The mixture was stirred for 14 h,and another 100 mg-portion was added. After maintaining the reaction atrt under N₂ for 24 h, the mixture was concentrated and poured into 1NNaOH (25 mL). The aqueous layer was washed with EtOAc (3×25 mL), and thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The resulting residue was purified by radialchromatography (5% MeOH in CH₂Cl₂) to afford solely1-(2,3-dihydro-1H-indol-5-yl)hexahydro-2H-azepin-2-one as a yellow foam(90 mg, 38%). ¹H NMR (CDCl₃) δ 7.24 (d, 1H), 7.17 (s, 1H), 7.06 (m, 1H),3.60–3.85 (m, 2H), 3.45 (m, 1H), 3.18 (m, 2H), 2.97 (m, 1H), 2.69 (br s,2H), 1.82 (br s, 6H).

Part D. To the product from Part C (90 mg, 0.39 mmol), was added3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylicacid (89 mg, 0.33 mmol), 3.0 mL of pyridine and 1.0 mL of DMF.1,3-Diisopropylcarbodiimide (0.056 mL, 0.36 mmol) was added, and theresulting solution was stirred for 14 h. The red mixture was poured into1N aqueous HCl (70 mL) and washed with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, and filtered.Concentration of the filtrate and purification of the resulting residueby preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA inCH₃CN/H₂O) gave1-(3-cyano-4-fluorophenyl)-5-{[6-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide(67, 29% mg) as a white foam. LC/MS (ESI⁺): 487.2 (M+H)⁺.

Part E. To the product from Part D (67 mg, 0.11 mmol) was added 6.3 mLof DMF and 2.5 mL of H₂O. Potassium carbonate (95 g, 0.69 mmol) andacetohydroxamic acid (26 mg, 0.34 mmol) were added, and the resultingmixture was warmed to 50° C. under an N₂ atmosphere. After 2 h, thereaction was cooled to rt and poured into EtOAc (50 mL). The organiclayer was washed with H₂O (2×15 mL), brine, and dried over Na₂SO₄.Filtration and concentration afforded a brown oily residue that waspurified by preparative LC/MS (C18 reverse phase, eluted with 0.05% TFAin CH₃CN/H₂O) to afford1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[6-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamidetrifluoroacetate (33 mg, 40%) as a white solid. LC/MS (ESI⁺): 500.2(M+H−TFA)⁺.

Example 181-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL,470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C.5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL)was added dropwise to the reaction. The reaction was warmed to rt andstirred overnight. Reaction was cooled to 0° C. and potassiumtert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction waswarmed to rt and stirred overnight. The reaction was concentrated andthen redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL),extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL),washed with brine (1×250 mL), and dried (Na₂SO₄). Purification by silicagel chromatography using 0%–100% ethyl acetate/hexane gradient as eluentto afford 51.03 g (81%): ¹H NMR (CDCl₃) δ 7.70 (d,j=8.4 Hz, 2H), 7.03(d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H),2.50–1.88 (m, 4H) ppm.

Part B. The above lactam intermediate from Part A (85.17 g, 282.8 mmol)and phosphorus pentachloride (205.91 g, 990.0 mmol) were dissolved intoCHCl₃ (750 mL) and refluxed for 3½ h. Reaction was poured over ice andthen quenched further with water, extracted with CHCl₃ (3×400 mL),washed with brine (1×400 mL), dried (MgSO₄), and concentrated. Thisresidue was dissolved in morpholine (400 mL) and refluxed overnight.Reaction was concentrated and purified by silica gel chromatographyusing 0%–100% ethyl acetate/hexane gradient as eluent to afford 68 g(63%): ¹H NMR (CDCl₃) δ 7.68 (d,j=8.8 Hz, 2H), 7.11 (d,j=8.8 Hz, 2H),5.66 (t,j=4.8 Hz, 1H), 3.82 (t,j=4.8 Hz, 4H), 3.77 (t,j=6.8 Hz, 2H),2.89 (t,j=4.8 Hz, 4H), 2.53–2.47 (m, 2H) ppm.

Part C. To p-anisidine (16 g, 0.129 mol) in conc. HCl (40 mL) and water(100 mL) at 0° C. was slowly added sodium nitrite (9.4 g, 0.136 mol) inwater (60 mL). The reaction was stirred cold for 0.5 h. To the abovereaction was poured a mixture of ethylchloroacetoacetate (22 g, 0.133mol), ethanol (100 mL), sodium acetate (32 g, 0.389 mmol), and water(400 mL). The reaction was stirred 2 h at rt. The precipitate wasfiltered-off and dried to afford the hydrazone as a red gum (30.3 g,91%): ¹H NMR (CDCl₃) δ 8.28 (s, 1H), 7.18 (d,j=9.1 Hz, 2H), 6.90(d,j=9.2 Hz, 2H), 4.41(q, j=8 Hz, 2H), 3.80 (s, 3H), 1.42 (t,j=6.9 Hz,3H) ppm.

Part D. To the hydrazone from Part C (0.7 g, 2.7 mmol) and themorpholine compound from Part B (0.7 g, 1.8 mol) in toluene (25 mL) wasadded triethylamine (2 mL, 14.2 mmol) and the reaction was heated toreflux for 6 h. The reaction was cooled to rt and water was added. Themixture was extracted with ethyl acetate, washed with water, 1N HCl,sat'd NaHCO₃ and dried (Na₂SO₄). Purification on silica gel using 3:2hexanes/ethyl acetate afforded a morpholine intermediate that wasdissolved in CH₂Cl₂ (50 mL) and TFA (2 mL). After 24 h the reaction wasdiluted with CH₂Cl₂, washed with water and sat'd NaHCO₃ and dried(Na₂SO₄) to afford 0.17 g (18%) foam: ¹H NMR (CDCl₃) δ 7.70 (d,j=8.5 Hz,2H), 7.47 (d,j=9.1 Hz, 2H), 7.09 (d,j=8.8 Hz, 2H), 6.93 (d,j=9.2 Hz,2H), 4.49(q, j=6.9 Hz, 2H), 4.12 (t,j=6.5 Hz, 2H), 3.81 (s, 3H), 3.34(t,j=6.6 Hz, 2H), 1.45 (t,j=6.9 Hz, 3H) ppm; Mass Spec ESI(M+H)⁺ 517.9.

Part E. To iodo compound from Part D (25 g, 0.048 mol) was addedγ-valerolactam (6.7 g, 0.067 mol), K₂CO₃ (8 g, 0.058 mol), degassed DMSO(100 mL) and CuI (1.84 g, 0.009 mol). The reaction was heated to 130° C.for 24 h. The reaction was cooled, partitioned with EtOAc/H₂O, extractedand dried (MgSO₄). Purification by silica gel chromatography using 0–10%MeOH/CH₂Cl₂ as eluent afforded 5 g (21%) of ethyl1-(4-methoxyphenyl)-7-oxo-6[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylateas a tan foam; ¹H NMR (CDCl₃) δ 7.49 (d,j=9.2 Hz, 2H), 7.35 (d,j=8.8 Hz,2H), 7.26 (d,j=8.1 Hz, 2H), 6.92 (d,j=8.8 Hz, 2H), 4.49(q,j=7.3 Hz, 2H),4.13 (t,j=6.6 Hz, 2H), 3.81 (s, 3H), 3.59 (m, 2H), 3.39 (t,j=6.6 Hz,2H), 2.55 (m, 2H), 1.91 (m, 4H), 1.45 (t,j=7.3 Hz, 3H) ppm.

Part F. To ester from Part E (4.8 g, 0.009 mol) was added 5% NH₃ inethylene glycol (40 mL) and the mixture was heated to 120° C. for 4 h insealed vessel. Water was added and the resulting solid was collected.Purification by silica gel chromatography using 0–10% MeOH/CH₂Cl₂ aseluent afforded 3.5 g of a white solid. A portion of the solid wasrecrystallized from CH₂Cl₂/EtOAc to afford 2.5 g of the title compound.The remaining solid and filtrate material was recrystallized fromisopropyl alcohol to afford an additional 0.57 g for a total of 3.07 g(68%): ¹H NMR (CDCl₃) δ 7.49 (d,j=8.8 Hz, 2H), 7.37 (d,j=9.1 Hz, 2H),7.26 (d,j=8.8 Hz, 2H), 6.98 (s, 1H) 6.95 (d,j=9.2 Hz, 2H), 6.28 (s, 1H),4.14 (t,j=6.6 Hz, 2H), 3.81 (s, 3H), 3.61 (m, 2H), 3.39 (t,j=6.6 Hz,2H), 2.63 (t,j=6.2 Hz, 2H), 1.96 (m, 4H) ppm.

Example 19 3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part A. 4-Methoxyphenyl hydrazine hydrochloride (3 g, 17 mmol) wastreated with glyoxylic acid monohydrate (1.6 g, 17 mmol) in H₂O withconc. HCl (1 mL). After 3 h a red precipitate was filtered off and driedto afford 3.13 g (93%) hydrazone.

Part B. The hydrazone from Part A (3.13 g, 16.1 mmol) was placed in DMF(20 mL), cooled to −5° C. and NBS (5.7 g, 32 mmol) in DMF (20 mL) wasadded slowly. The reaction was held at rt 15 min and then3-(4-morpholinyl)-1-(4-nitrophenyl)-5,6-dihydro-2(1H)-pyridinone(Example 1 Part A) (4.8 g, 16 mmol) was added. TEA (4.5 mL, 32 mmol) intoluene (50 mL) was added dropwise and the reaction stirred at rt for 24h. The morpholine intermediate was extracted with EtOAc, washed withH₂O, dried (Na₂SO₄) then purified by silica gel chromatography using 1:1Hexanes/EtOAc as eluent to afford a foam.

Part C. The morpholine intermediate from Part B was treated with TFA (5mL) in CH₂Cl₂(30 mL) for 24 h. Dilution with CH₂Cl₂, washing with H₂O,sat'd NaCl and drying (Na₂SO₄) afforded 2.29 g (32%) of a tan foam; ¹HNMR (CDCl₃) δ 8.25 (d,j=9.1 Hz, 2H), 7.51 (d,j=8.8 Hz, 2H), 7.46(d,j=9.1 Hz, 2H), 6.94 (d,j=9.2 Hz, 2H), 4.22 (t,j=6.6 Hz, 2H), 3.82 (s,3H), 3.04 (t,j=6.6 Hz, 2H) ppm.

Part D. The nitro compound from Part C (0.67 g, 1.5 mmol) was heated toreflux in MeOH (25 mL) containing 5% Pt/C (0.1 g) and ammonium formate(0.25 g) for 24 h. The reaction was cooled, filtered and concentrated toafford 0.61 g (98%) aniline; Mass Spec (M+H)⁺ (413–415).

Part E. The aniline from Part D was converted to the lactam as describedfor the aniline in the previous Example 1 Part D to afford the titlecompound. ¹H NMR (CDCl₃) δ 7.46 (d,j=9.1 Hz, 2H), 7.34 (d,j=8.8 Hz, 2H),7.26 (d,j=8.8 Hz, 2H), 6.91 (d,j=9.1 Hz, 2H), 4.14 (t,j=6.6 Hz, 2H), 3.8(s, 3H), 3.59 (m, 2H), 2.98 (t,j=6.6 Hz, 2H), 2.55 (m, 2H), 1.95 (m, 4H)ppm. HRMS for C₂₄H₂₄Br₁N₄O₃ (M+H)⁺ 495.1032.

Example 201-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(4-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

To crude3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(Example 19) (0.19 g, 0.4 mmol) was added toluene (25 mL), ethanol (10mL), 2M Na₂CO₃(1 mL), and pyridine-4-boronic acid(60 mg, 0.48 mmol). Themixture was degassed with N₂ and tetrakistriphenylphosphine palladium(25 mg) was added and the reaction heated to reflux 24 h. The reactionwas filtered, concentrated and extracted with EtOAc and dried (MgSO₄).Purification by HPLC and freeze-drying afforded 10 mg (4%) of the titlecompound; HRMS (M+H)⁺ for C₂₉H₂₈N₅O₃ was 494.2183; ¹H NMR(CDCl₃+DMSO-d6) δ 8.88 (d,j=6.6 Hz, 1H), 8.22 (d,j=6.6 Hz, 1H),7.30–7.06 (m, 6H), 6.74 (d,j=8.7 Hz, 2H), 3.98 (t,j=6.6 Hz, 2H), 3.60(s, 3H), 3.12 (t,j=6.6 Hz, 2H), 2.36 (m, 4H), 1.73 (m, 4H) ppm.

Example 211-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(4-pyridinyl-N-oxide)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The pyridine compound TFA salt of Example 20 (40 mg, 0.065 mmol) wasfree-based with sat'd aqueous NaHCO₃ and extracted into ethyl acetateand dried (MgSO₄). The pyridine compound was dissolved in CH₂Cl₂ andexcess 50% 3-chloroperbenzoic acid (50 mg) was added. The reaction wasstirred 3 h, washed with sat'd aqueous NaHCO₃ and dried (Na₂SO₄).Purification by HPLC and freeze-drying afforded 16 mg (48%) of the titlecompound; HRMS (M+H)⁺ for C₂₉H₂₈N₅O₄ was 510.2145; ¹H NMR (CDCl₃) δ 8.49(d,j=6.9 Hz, H), 7.93 (d,j=7 Hz, 2H), 7.51 (d,j=8.8 Hz, 2H), 7.37(d,j=8.8 Hz, 2H), 7.28 (d,j=8.8 Hz, 2H), 6.97 (d,j=8.8 Hz, 2H), 4.22(t,j=6.6 Hz, 2H), 3.83 (s, 3H), 3.61 (m, 2H), 3.30 (t,j=6.6 Hz, 2H),2.58 (m, 2H), 1.96 (m, 4H) ppm.

Example 221-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(3-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

To3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(Example 19)(0.23 g, 0.46 mmol) was added 3-tributylstannylpyridine(0.222 g, 0.61 mmol) and toluene (25 mL). The mixture was degassed withN₂ for 10 min, then tetrakistriphenylphosphine palladium (10 mg) wasadded. The reaction was heated to reflux for 3 h. The cooled reactionwas diluted with ethyl acetate then, washed sequentially with sat'daqueous KF, brine and dried (MgSO₄). Purification by silica gelchromatography using 0–5% MeOH/CH₂Cl₂ (1% NH₃) as eluent and conversionto the TFA salt before freeze-drying afforded 0.28 g (81%) of the titlecompound: HRMS (M+H)⁺ for C₂₉H₂₈N₅O₃ was 494.2191; ¹H NMR (DMSO-d6) δ9.09 (d,j=1.8 Hz, 1H), 8.76 (dd,j=5.2.1.5 Hz, 1H), 8.47 (d,j=8 Hz, 1H),7.81 (dd,j=5.2, 7.7 Hz, 1H), 7.55 (d,j=8.8 Hz, 2H), 7.39 (d,j=8.8 Hz,2H), 7.31 (d,j=8.8 Hz, 2H), 7.03 (d,j=9.2 Hz, 2H), 4.15 (t,j=6.6 Hz,2H), 3.81 (s, 3H), 3.62 (t,j=5.5 Hz, 2H) 3.30 (t,j=6.6 Hz, 2H), 2.41(t,j=6.2 Hz, 2H), 1.85 (m, 4H) ppm.

Example 231-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(3-pyridinyl-N-oxide)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

This compound was prepared by the same procedure as Example 21: HRMS(M+H)⁺ for C₂₉H₂₈N₅O₄ was 510.2121; ¹H NMR (DMSO-d6) δ 8.57 (s, 1H),8.25 (d,j=7 Hz, 1H), 7.91 (m, 1H), 7.71 (m, 1H), 7.54 (d,j=9.2 Hz, 2H),7.38 (d,j=8.8 Hz, 2H), 7.31 (d,j=8.8 Hz, 2H), 7.02 (d,j=8.8 Hz, 2H),4.11 (t,j=6.6 Hz, 2H), 3.80 (s, 3H), 3.58 (t,j=5.5 Hz, 2H), 3.25 (m,2H), 2.40 (t,j=6 Hz, 2H), 1.86 (m, 4H) ppm.

Example 241-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(2-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]-7-oneTrifluoroacetic acid salt

To3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]-7-one(Example 21)(0.21 g, 0.43 mmol) was added 2-tributylstannylpyridine(0.26 g, 0.55 mmol) and toluene (25 mL). The mixture was degassed withN₂ for 10 min, then tetrakistriphenylphosphine palladium (10 mg) wasadded. The reaction was heated to reflux for 24 h. The cooled reactionwas diluted with ethyl acetate then, washed sequentially with sat'daqueous KF, brine and dried (MgSO₄). Purification by silica gelchromatography using 0–5% MeOH/CH₂Cl₂ (1% NH₃) as eluent, then by HPLCand freeze-drying afforded 0.26 g (58%) of the title compound: HRMS(M+H)⁺ for C₂₉H₂₈N₅O₃ was 494.2192; ¹H NMR (DMSO-d6) δ 8.68 (d,j=4 Hz,1H), 8.05 (d,j=8.1 Hz, 1H), 7.95 (dt,j=1.8, 7.7 Hz, 1H), 7.55 (d,j=8.8Hz, 2H), 7.43 (m, 1H), 7.39 (d,j=8.8 Hz, 2H), 7.30 (d,j=8.8 Hz, 2H),7.02 (d,j=9.2 Hz, 2H), 4.13 (t,j=6.6 Hz, 2H), 3.81 (s, 3H), 3.61(t,j=4.8 Hz, 2H) 3.43 (t,j=6.6 Hz, 2H), 2.41 (t,j=6 Hz, 2H), 1.86 (m,4H) ppm.

Example 25 1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (Example 21)(0.15 g, 0.3 mmol), dimethylamine (2MTHF, 1.5 mL, 3 mmol), sodium t-butoxide (88 mg, 0.9 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (7 mg), was addedtoluene/dioxane (1:1) (15 mL) and the mixture was degassed with N₂.Pd₂(dba)₃ was added and the reaction was heated to 85° C. for 24 h. Thereaction was cooled, diluted with ethyl acetate and filtered throughCelite® Purification by HPLC and freeze-drying afforded 25 mg (18%) ofthe title compound; HRMS (M+Na)⁺ for C₂₄H₂₄NaN₄O₃ was 439.1726; ¹H NMR(CDCl₃) δ 7.59 (s, 1H), 7.47 (d,j=8.8 Hz, 2H), 7.36 (d,j=8.8 Hz, 2H),7.26 (d,j=9.1 Hz, 2H), 6.92 (d,j=9.2 Hz, 2H), 4.10 (t,j=6.6 Hz, 2H),3.60 (m, 2H), 3.81 (s, 3H), 3.03 (t,j=6.6 Hz, 2H), 2.57 (m, 2H), 1.94(m, 4H) ppm.

Example 261-(4-methoxyphenyl)-7-oxo-6-[5-(2-oxo-1-piperidinyl)2-pyridinyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide,trifluoroacetic acid salt

Part A. To valerolactam (5.6 g, 55 mmol) in CHCl₃ was added PCl₅ (34.6g, 166 mmol) and the reaction was heated to reflux 24 h. The reactionwas cooled, quenched with H₂O, extracted with CHCl₃ and dried (MgSO₄) toafford crude 3,3-dichloro-2-piperidinone.

Part B. To the 3,3-dichloro-2-piperidinone (55 mmol) from Part A wasadded CCl₄ (250 mL), AlCl₃ (22 g, 166 mmol) and the reaction was heatedto reflux 24 h. The reaction was cooled and added to 3N NaOH (200 mL)and NH₄Cl (40 g). The resultant emulsion was filtered through Celite®and the aqueous layer extracted with CH₂Cl₂ and dried (MgSO₄) to afford3.4 g (46%) of 3-chloro-5,6-dihydro-2(1H)-pyridinone; ¹H NMR (CDCl₃) δ6.80 (t,j=4.7 Hz, 1H), 6.60 (s, 1H), 3.51 (m, 2H), 2.51 (m, 2H) ppm.

Part C. The 3-chloro-5,6-dihydro-2(1H)-pyridinone (1.5 g, 11.4 mmol) washeated to reflux in toluene (50 mL), with TEA(5 mL, 34 mmol) and ethyl(2Z)-chloro[4-methoxyphenyl)hydrazono]ethanoate (Example 19 Part B)(4 g,15.6 mmol) for 24 h. A tan precipitate was filtered off and the filtratepurified through silica gel using 1:1 Hexane/EtOAc as eluent to afford atotal of 1.4 g (38%) ethyl1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-carboxylate;¹H NMR (CDCl₃) δ 7.51 (d,j=9.2 Hz, 2H), 6.96 (d,j=9.2 Hz, 2H), 5.59 (s,1H), 4.48(q,j=7.3 Hz, 2H), 3.85 (s, 3H), 3.66 (dt,j=3 Hz, 2H), 3.22(t,j=6.9 Hz, 2H), 1.44 (t,j=7 Hz, 3H) ppm.

Part D. To the ethyl1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-carboxylate(0.49 g, 1.55 mmol) was added CsCO₃ (0.76 g, 2.3 mmol),9,9-dimethyl-4,5-bis(diphenyphosphino)xanthene (70 mg, 0.11 mmol), andpalladium(II) acetate (18 mg, 0.08 mmol) and the mixture was flushedwith N₂. Dioxane (15 mL) and 2-bromo-5-nitropyridine (0.315 g, 1.55mmol) were added and the reaction heated to 75° C. for 24 h. Thereaction was filtered, partitioned between EtOAc and H₂O and extracted.The organic layer was dried (MgSO₄). Purification by chromatography onsilica gel using 2:1 hexane/EtOAc as eluent afforded 0.62 g (92%) of thenitro compound; Mass Spec (M+H)⁺ 438.1.

Part E. The nitro compound from Part D (0.61 g, 1.4 mmol) was reducedwith iron powder (0.9 g, 16 mmol) in acetic acid (15 mL) at 90° C. for1.5 h. The reaction was cooled, filtered, concentrated, dissolved inCH₂Cl₂ and washed with sat'd NaHCO₃ and dried (MgSO₄) to afford 0.46 g(81%) of the aniline as a yellow solid; Mass Spec (M+H)⁺ 408.1.

Part F. To the aniline from Part E(0.27 g, 0.66 mmol) was added5-bromovaleryl chloride (0.16 g, 0.8 mmol) and TEA (0.23 mL, 1.65 mmol)in THF (20 mL) and the reaction was stirred 24 h. Potassium t-butoxide(0.24 g, 1.99 mmol) was added and the reaction was stirred 72 h. Thereaction was quenched with water and extracted with EtOAc, dried (MgSO₄)and chromatographed on silica eluting with 1:1 Hexanes/EtOAc to afford0.17 g (53%) of the lactam as a white solid; Mass Spec (M+H)⁺ 490.2.

Part G. To the lactam from Part F (0.17 g, 0.34 mmol) in DMF (2.5 mL)was added formamide (0.14 mL, 3.5 mmol) and 25% NaOMe/MeOH (0.5 mL). Thereaction was stirred 24h, concentrated, and purification by HPLC andfreeze-drying afforded 10 mg (5%) of the title compound; HRMS (M+H)⁺ forC₂₄H₂₅N₆O₄ was 461.1918.

Example 271-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part A. Ethyl6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(0.57 g, 1.1 mmol), 2-hydroxypyridine (0.125 g, 1.3 mmol), K₂CO₃ (0.18g, 1.3 mmol) were combined in DMSO (5 mL) and degassed with N₂. Copper(I) iodide (41 mg, 0.21 mmol) was added and the reaction was heated to130° C. for 24 h. The reaction was quenched with dilute NH₄OH solutionand filtered. The filtrate was extracted with EtOAc and dried (MgSO₄).Purification on silica gel using 0–5% MeOH/CH₂Cl₂ as eluent afforded 70mg (13%) of the ester; Mass Spec (M+H)+ 485.2.

Part B. To the ester from Part A (0.07 g, 0.144 mmol) in formamide (4mL) and DMF (3 mL) was added 1 drop of 25% NaOMe/MeOH. The reaction wasstirred 48 h, then partitioned between EtOAc and water. Extraction withEtOAc, drying (MgSO₄) and purification by HPLC afforded 25 mg (38%) ofthe title compound; ¹H NMR (DMSO-d6) δ 7.49 (d,j=9.2 Hz, 2H), 7.48 (m,2H), 7.41 (d,j=8.8 Hz, 2H), 7.40 (m, 1H), 7.28 (m, 1H), 6.96 (d,j=9.2Hz, 2H), 6.90 (s, 1H), 6.69 (d,j=8.8 Hz, 1H), 6.27 (t,j=6 Hz, 1H), 5.55(s, 1H), 4.19 (t,j=6.6 Hz, 2H), 3.83 (s, 3H), 3.43 (t,j=6.6 Hz, 2H) ppm.

Example 281-(4-methoxyphenyl)-3-(methylsulfonyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part A. To p-anisidine (4.39 g, 3.6 mmol) in conc. HCl (9.2 mL) andwater (20 mL) at 0° C. was slowly added sodium nitrite (2.58 g, 3.7mmol) in water (20 mL). The reaction was stirred cold for 0.5 h. Theabove mixture was poured into a mixture of 3-chloromethanesulphonylacetone (Grossert et. al., Can. J. Chem. 62, 1984, 798)(6.1 g, 3.5mmol), acetone (50 mL), sodium acetate (6.7 g, 8.2 mmol), and water (100mL). The reaction was stirred 4 h at rt The precipitate was filtered-offand dried to afford the hydrazone as a red solid(5.28 g, 57%); ¹H NMR(CDCl₃) δ 8.05 (s, 1H), 7.12 (d,j=9.2 Hz, 2H), 6.91 (d,j=8.8 Hz, 2H),3.80 (s, 3H), 3.23 (s, 3H) ppm.

Part B. To the hydrazone from Part A (0.78 g, 2.9 mmol) and3-(4-morpholinyl)-1-(4-nitrophenyl)-5,6-dihydro-2(1H)-pyridinone (0.9 g,2.9 mmol) in toluene (30 mL) was added triethylamine (1 mL, 7.2 mmol)and the reaction was heated to reflux for 18 h. The reaction was cooledto rt and excess TFA was added. After 24 h the reaction was diluted withethyl acetate, washed with water and sat'd NaHCO₃ and dried (MgSO₄).Purification on silica gel using 1:1 hexanes/ethyl acetate afforded 0.63g (48%) of a tan foam: ¹H NMR (CDCl₃) δ 8.26 (d,j=9.1 Hz, 2H), 7.52(d,j=9.2 Hz, 2H), 7.46 (d,j=8.8 Hz, 2H), 6.97 (d,j=8.8 Hz, 2H), 4.24(t,j=6.6 Hz, 2H), 3.83 (s, 3H), 3.41 (t,j=6.6 Hz, 2H), 3.32 (s, 3H) ppm;Mass Spec ESI(M+H)⁺ 556.1.

Part C. The nitro compound of Part B (0.63 g) was hydrogenated inethanol/ethyl acetate/HCl and 20 mg of 10% palladium on carbon at 45 psifor 3 h. The reaction was filtered and concentrated to afford the amine.To the above amine (400 mg) in THF (20 mL), 5-bromovaleryl chloride(0.14 mL, 1.0 mmol) and triethylamine (0.32 mL, 2.2 mmol) were added andstirred 24 h. Potassium t-butoxide (0.33 g, 2.6 mmol) was added and thereaction was stirred 72 h. The reaction was quenched with water,extracted with ethylacetate, washed with brine and dried (MgSO₄).Purification on silica gel using 1:2 hexanes/ethyl acetate to 2%MeOH/ethyl acetate and recrystallization from isopropyl alcohol afforded0.1 g (23%): M.P.=243–245° C.; ¹H NMR (CDCl₃) 87.49 (d,j=8.8 Hz, 2H),7.34 (d,j=9.1 Hz, 2H), 7.27 (d,j=8.7 Hz, 2H), 6.95 (d,j=8.8 Hz, 2H),4.16 (t,j=6.6 Hz, 2H), 3.82 (s, 3H), 3.61 (t,j=5.9 Hz, 2H), 3.57(t,j=6.6 Hz, 2H), 3.31 (s, 3H), 2.57 (t,j=5.5 Hz, 2H), 1.95 (m, 4H) ppm.

Example 291-(4-methoxyphenyl)-6-(4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(2-pyridinyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

Part A. 4-Methoxyphenyl hydrazine hydrochloride (3 g, 17 mmol) in H₂O(28 mL) was treated with glyoxylic acid monohydrate (1.6 g, 17 mmol) inH₂O (20 mL) with conc. HCl (1.8 mL). After 2 h, a red precipitate wasfiltered off and dried to afford 3 g (89%) hydrazone.

Part B. The hydrazone from Part A (1 g, 5.0 mmol) was placed in DMF (10mL), cooled to −5° C. and NBS (1.8 g, 10 mmol) in DMF (10 mL) was addedslowly. The reaction was held at rt for 15 min and then3-(4-morpholinyl)-1-(4-iodophenyl)-5,6-dihydro-2(1H)-pyridinone (1.97 g,5.0 mmol) was added. TEA (1.4 mL, 32 mmol) in toluene (25 mL) was addeddropwise and the reaction stirred at rt for 24 h. The morpholineintermediate was extracted with EtOAc, washed with H₂O, dried (Na₂SO₄).The morpholine intermediate was treated with TFA (5 mL) in CH₂Cl₂ (30mL) for 24 h. Dilution with CH₂Cl₂, washing with H₂O, sat'd NaCl anddrying (Na₂SO₄) afforded a foam. Purification on silica gel using 2:1hexanes/ethyl acetate and recrystallization from CH₂Cl₂/Hexanes afforded1.4 g (55%); Mass Spec (M+H)⁺ 524–526.

Part C. The compound from Part B (0.32 g, 0.6 mmol), 2-hydroxypridine(35 mg, 0.36 mmol), K₂CO₃ (0.135 g, 0.97 mmol) were combined in DMSO (5mL) and degassed with N₂. Copper (I) iodide (23 mg, 0.12 mmol) was addedand the reaction was heated to 130° C. for 24 h. The reaction wasquenched with dilute NH₄OH solution and filtered. The filtrate wasextracted with EtOAc and dried (Na₂SO₄). Purification on silica gelusing 0–2% MeOH/CH₂Cl₂ as eluent afforded 130 mg (43%) of the bromocompound; Mass Spec (M+H)⁺ 513.3–515.2.

Part D. To the compound from Part C (0.13 g, 0.26 mmol) was added2-tributylstannylpyridine (0.16 g, 0.34 mmol) and toluene (25 mL). Themixture was degassed with N₂ for 10 min, then tetrakistriphenylphosphinepalladium (10 mg) was added. The reaction was heated to reflux for 24 h.The cooled reaction was diluted with ethyl acetate then, washedsequentially with sat'd aqueous KF, brine and dried (MgSO₄).Purification by silica gel chromatography using 0–5% MeOH/CH₂Cl₂ (1%NH₃) as eluent, then by HPLC and freeze-drying afforded 0.20 mg (12%) ofthe title compound: HRMS (M+H)⁺ for C₂₉H₂₄N₅O₃ was 490.1880; ¹H NMR(CDCl₃) δ 8.85 (m, 1H), 8.11 (m, 2H), 7.57 (d,j=9.2 Hz, 2H), 7.55 (m,2H), 7.51 (d,j=9.1 Hz, 2H), 7.42 (d,j=8.8 Hz, 2H), 7.41 (m, 1H), 6.97(d,j=8.8 Hz, 2H), 6.84 (d,j=8.8 Hz, 2H), 6.42 (m, 1H), 4.24 (t,j=6.6 Hz,2H), 3.83 (s, 3H), 3.47 (t,j=6.6 Hz, 2H) ppm.

Example 301-[3-aminomethylphenyl]-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

The nitrile precursor was prepared following the general [3+2]procedurewith the corresponding trifluoromethyl hydrazone moiety and themorpholine-enamine described in Example 3. Ullman coupling withδ-valerolactam afforded the desired nitrile precursor. Reduction of thebenzonitrile as in Example 4 part B followed by purification via prepHPLC afforded the desired benzylamine analog. LRMS 484 (M+H).

Example 313-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzamide

The benzonitrile precursor from Example 30 was hydrolyzed with hydrogenperoxide in sodium hydroxide to provide the title compound which onpurification via prep HPLC afforded pure compound. LRMS 498 (M+H).

Example 321-(3-chlorophenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

The title compound was prepared following the general proceduredescribed previously. HRMS (ESI⁺): 464.1497. (M+H)⁺. ¹H NMR (CDCl₃) δ7.60 (s, 1H), 7.50 (d, 1H), 7.39–7.25 (m, 6H), 6.96 (s, 1H), 5.96 (s,1H), 4.13 (t, 2H), 3.62 (t, 2H), 3.37 (t, 2H), 2.57 (t, 2H), 1.96–1.93(m, 4H).

Example 331-(3-chlorophenyl)-7-oxo-6-[4-(2-oxo-1(2H)pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

The title compound was prepared following the general proceduredescribed previously. HRMS (ESI⁺): 460.1156. (M+H)⁺. ¹H NMR (CD₃OD) δ7.85 (s, 1H), 7.72 (s, 1H), 7.71–7.44 (m, 8H), 6.64 (d, 1H), 6.48 (t,1H), 4.20 (t, 2H), 3.37 (t, 2H).

Example 341-(3-chlorophenyl)-N,N-dimethyl-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

The title compound was prepared following the general proceduredescribed previously. HRMS (ESI⁺): 492.1807. (M+H)⁺. ¹H NMR (CD₃OD) δ7.67 (s, 1H), 7.57–7.53 (m, 1H), 7.47–7.40 (m, 4H), 7.32 (d, 2H), 4.14(t, 2H), 3.67 (t, 2H), 3.39 (s, 3H), 3.19 (t, 2H), 3.14 (s, 3H), 2.53(t, 2H), 1.97–1.95 (m, 4H).

Example 351-(3-chloro-4-fluorophenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

The title compound was prepared following the general proceduredescribed previously. LRMS (ESI⁺): 482.3. (M+H)⁺. ¹H NMR (CDCl₃) δ7.68–7.65 (m, 1H), 7.52–7.46 (m, 1H), 7.34 (d, 2H), 7.28 (d, 2H), 7.17(t, 1H), 6.86 (s, 1H), 5.74 (s, 1H), 4.13 (t, 2H), 3.62 (t, 2H), 3.38(t, 2H), 2.58 (t, 2H), 1.96–1.94 (m, 4H).

Example 361-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile

To dimethylformamide (0.2 mL, 2.6 mmol) in CH₃CN (20 mL) at 0° C. wasadded oxalyl chloride (0.23 mL, 2.6 mmol) and the reaction was stirred0.5 h. The amide from Example 27 was added and the reaction was stirredcold 0.5 h. Pyridine (0.37 mL, 4.6 mmol) was added and the reaction wasallowed to warm to rt and stirred for 24 h. The solvent was stripped,the residue was partitioned between CH₂Cl₂ and 1N HCl, and the layersseparated. The aqueous layer was basified with 1N NaOH and extractedwith EtOAc. The organic layers were combined and dried (MgSO₄).Purification by chromatography on silica gel using 3% MeOH in CH₂Cl₂ andrecrystallization from CH₂Cl₂/hexanes afforded 117 mg (89%); ¹H NMR(CDCl₃) δ 7.50 (d,j=8.8 Hz, 2H), 7.44 (m, 5H), 7.31 (m, 1H), 6.97(d,j=9.2 Hz, 2H), 6.71 (d,j=9.5 Hz, 2H), 6.28 (m, 1H), 4.24 (t,j=6.6 Hz,2H), 3.85 (s, 3H), 3.24 (t,j=6.6 Hz, 2H) ppm; LRMS (M+H)+ 438.4.

Example 371-(3-amino-1H-indazol-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

1-(3-Cyano-4-fluorophenyl)-6-[4-iodophenyl]-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(58mg, prepared following the general procedure described for Examples 3–5)was dissolved in 1-butanol (5 mL). To the solution was added hydrazinemonohydrate (0.5 mL). The reaction mixture was brought to reflux for 4h, cooled to rt, and the solvent removed. The residue was purified usingHPLC (RP gradient) to give the title compound as its TFA salt (25 mg,42%). HRMS (ESI⁺): 485.2050 (M+H)⁺. ¹H NMR (CD₃OD) δ 8.06 (s, 1H), 7.78(d, 2H), 7.74 (d, 1H), 7.44–7.40 (m, 3H), 7.30 (d, 2H), 4.18(t, 2H),3.65 (t, 2H), 3.38 (t, 2H), 2.52 (t, 2H), 1.98–1.96 (m, 4H).

Example 381-(3-amino-1,2-benzisoxazol-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

The title compound was made from its corresponding 4-fluoro-3-cyanointermediate (previously described for Examples 3–5). HRMS (ESI⁺):486.1885 (M+H)⁺. ¹H NMR (CD₃OD) δ 7.99 (s, 1H), 7.78 (d, 1H), 7.48–7.40(m, 4H), 7.30 (d, 2H), 4.16 (t, 2H), 3.65 (t, 2H), 3.31 (t, 2H), 2.50(t, 2H), 1.96–1.94 (m, 4H).

Example 395-chloro-N-[5-chloro-3-methoxy-2-({[4-(2-oxo-1-piperidinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide

Part A. To a solution of 4-iodomethylbenzoate is added δ-valerolactam (1eq), cesium carbonate (1.5 eq) followed by catalytic CuI. The reactionmixture is heated at 100° C. overnight, cooled, and quenched with water.The organics are extracted with ethylacetate, dried (magnesium sulfate),and evaporated to afford crude product which is purified via silica gelcolumn chromatography (hexane:ethylacetate) to afford the coupledproduct.

Part B. To the product from part A in THF is added LiOH (excess of 1 eq)and water. The reaction mixture is stirred at rt overnight and quenchedwith dilute HCl. The desired carboxylic acid intermediate is extractedwith ethyl acetate, dried, and evaporated to afford the product.

Part C. To the product from part B in dichloromethane is added 1equivalent of thionyl chloride along with cat. DMF. The reaction mixtureis stirred at rt overnight and concentrated to afford4-(2-oxo-piperidin-1-yl)-benzoyl chloride.

Part D. To a solution of 2-nitro-5-chloro-benzoylchloride indichloromethane is added 2-amino-5-chloropyridine (1 eq) and DMAP(excess of 2 eq). The reaction mixture is stirred at rt overnight,quenched with water, and the organics extracted with ethylacetate anddried (magnesium sulfate). Evaporation affords the coupled product.

Part E. The product from part A is dissolved in ethyl acetate. To thissolution are added 3 equivalents of tin chloride, and the reactionmixture is stirred at rt for 4 h. The reaction mixture is quenched withsat'd ammonium hydroxide solution and the organics extracted with ethylacetate, dried, and evaporated to afford the anilino derivative.

Part F. The product from part B was dissolved in dichloromethane and tothis solution is added 4-(2-oxo-piperidin-1-yl)-benzoyl chloride (1 eq)and DMAP (excess of 2 eq). The reaction mixture is stirred at rtovernight, concentrated, and purified via reverse phase prep. HPLC(acetonitrile/water/TFA) to afford the title compound.

Example 405-chloro-N-[5-chloro-3-methoxy-2-({[4-(2-oxo-1(2H)-pyridinyl)phenyl]amino}carbonyl)phenyl]-2-pyridinecarboxamide

Part A. To a solution of 4-iodomethylbenzoate is added 2-hydroxypyridine(1 eq), cesium carbonate (1.5 eq) followed by catalytic CuI. Thereaction mixture is heated at 100° C. overnight, cooled, and quenchedwith water. The organics are extracted with ethyl acetate, dried, andevaporated to afford crude product which is purified via silica gelcolumn chromatography (hexane:ethylacetate) to afford the coupledproduct.

Part B. To the product from part A in THF is added LiOH (excess of 1 eq)and water. The reaction mixture is stirred at rt overnight and quenchedwith dilute HCl. The desired carboxylic acid intermediate is extractedwith ethyl acetate, dried, and evaporated to afford the product.

Part C. To the product from part B in dichloromethane is added 1equivalent of thionyl chloride along with cat. DMF. The reaction mixtureis stirred at rt overnight and concentrated to afford4-(2-oxo-pyridin-1-yl)-benzoyl chloride.

Part D. To a solution of 2-nitro-5-chloro-benzoylchloride indichloromethane is added 2-amino-5-chloropyridine (1 eq) and DMAP(excess of 2 eq). The reaction mixture is stirred at rt overnight,quenched with water, and the organics extracted with ethylacetate anddried (magnesium sulfate). Evaporation affords the coupled product.

Part E. The product from part A was dissolved in ethyl acetate. To thissolution is added 3 equivalents of tin chloride, and the reactionmixture stirred at rt for 4 h. The reaction mixture is quenched withsat'd ammonium hydroxide solution and the organics extracted with ethylacetate, dried, and evaporated to afford the anilino product.

Part F. The product from part B was dissolved in dichloromethane and tothis solution is added 4-(2-oxo-pyridin-1-yl)-benzoyl chloride (1 eq)and DMAP (excess of 2 eq). The reaction mixture is stirred at rtovernight, concentrated, and purified via reverse phase prep. HPLC(acetonitrile/water/TFA) to afford the title compound.

Examples 41–53

Examples 41–53, shown below, can be prepared by following the proceduresof Examples 37–38.

Examples 54–70

Examples 54–70, shown below, can be prepared by following the proceduresof Examples 37–38 and using commercially available amino-nicotinicacids.

Example 71 Methyl2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-oxopropanoate

Part A. In a flame-dried 1-L flask was combined anhydrous methyl alcohol(1.4 L), 4-methoxyphenylhydrazine hydrochloride (25 g, 140 mmol),4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (30 g, 140 mmol), andtrifluoroacetic acid (1.1 mL, 14 mmol). The resulting red slurry wasmaintained at rt for 14 h. A 50% solution of isopropyl alcohol/water(500 mL) was then added, and the mixture was stirred vigorously for 5min. The mixture was filtered; additional material precipitated from thefiltrate upon standing, and the new mixture was filtered. After another3 h, the resulting filtrate was filtered a third time, and the combinedbeige solid was oven dried under vacuum to afford5-(2-furyl)-1-(4-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazole (42 g,96%) as a light brown solid. ¹H NMR (CDCl₃) δ 7.42(m, 1H), 7.35 (d, 2H),6.98 (d, 2H), 6.89 (s, 1H), 6.33 (dd, 1H), 5.90 (d, 1H), 3.88 (s, 3H).

Part B. To the product from Part B (20 g, 65 mmol) was added water (410mL), 5% aqueous sodium dihydrogenphosphate (270 mL), and tert-butanol(410 mL). The resulting mixture was warmed to 60° C., and potassiumpermanganate (63, 400 mmol) was added over a period of 1.5 h. After anadditional 10 min, the resulting purple slurry was cooled to 0° C., andthe reaction was quenched by the addition of 400 mL of saturated aqueoussodium bisulfite. The resulting brown slurry was filtered, washed with500 mL of water, and the filtrate was acidified to pH 1 withconcentrated aqueous hydrogen chloride. The aqueous layer was extractedwith ethyl acetate (6×150 mL), and the combined organic layers werewashed with saturated aqueous sodium chloride, dried over sodiumsulfate, and filtered. Concentration afforded1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(16 g, 85%) as a light yellow solid. MS (APCI⁺): 328.2 (M+H+CH₃CN)⁺. ¹HNMR (CDCl₃) δ 7.37 (d, 2H), 7.32 (s, 1H), 6.97 (d, 2H), 3.88 (s, 3H).

Part C. To a solution of 2-fluoro-4-iodo-1-methylbenzene (50 g, 210mmol) in anhydrous acetone (490 mL) was added N-bromosuccinimide (42 g,230 mmol) and 2,2′-azobisiso-butyronitrile (100 mg, 0.60 mmol). Theresulting solution was heated to reflux and maintained under refluxconditions for 5 h. The reaction was then cooled, concentrated, andfiltered. The filtrate was concentrated, and the resulting dark redresidue was purified by flash column chromatography (10% ethyl acetatein hexanes) to afford a 4:1 mixture (58 g) of1-(bromomethyl)-2-fluoro-4-iodobenzene (49 g, 73%) and2-fluoro-4-iodo-1-methylbenzene (9 g, 17%) as a red solid. ¹H NMR(product) (CDCl₃) δ 7.40–7.49 (m, 2H), 7.13 (t, 1H), 4.45 (s, 2H).

Part D. To the product from Part C (58 g, 140 mmol) in toluene (500 mL)and water (500 mL) was added sodium cyanide (34 g, 700 mmol) andtetrabutylammonium bromide (23 g, 70 mmol). The resulting mixture washeated to reflux and maintained under reflux condition for 14 h. Thedark brown mixture was then cooled, and the layers were separated. Theaqueous layer was washed with ethyl acetate (200 mL), and the combinedorganic layers were washed with saturated aqueous sodium chloride anddried over sodium sulfate. The organic layers were concentrated, and theresulting residue was purified by flash column chromatography (10% ethylacetate in hexanes) to give (2-fluoro-4-iodophenyl)-acetonitrile (20 g,54%) as a yellow solid. ¹H NMR (CDCl₃) δ 7.54 (dd, 1H), 7.49 (dd, 1H),7.18 (t, 1H), 3.72 (s, 2H).

Part E. To the product from Part D (20 g, 77 mmol) was added ethylalcohol (470 mL), water (230 mL), and sodium hydroxide (31 g, 770 mmol).The resulting mixture was heated to reflux and maintained under refluxconditions for 2 h. The reaction was then cooled, concentrated, andacidified to pH 1 with concentrated aqueous hydrochloric acid. Theresulting mixture was filtered, and the filter cake was dried in avacuum oven to afford (2-fluoro-4-iodophenyl)acetic acid (21 g, 96%) asyellow solid. ¹H NMR (CDCl₃) δ 7.43–7.48 (m, 2H), 7.00 (t, 1H), 3.67 (s,2H).

Part F. To the product from Part E (10 g, 36 mmol) was added methylalcohol (25 mL) and benzene (250 mL). The resulting solution was cooledto 0° C., and (trimethylsilyl) diazomethane (9 mL, 38 mmol; 2.0 M inhexanes) was added dropwise over 15 min. After 1 h, the reaction wasconcentrated, and the resulting residue was purified by flash columnchromatography (10–20% ethyl acetate in hexanes) to afford methyl(2-fluoro-4-iodophenyl)acetate (6.9 g, 66%) as a yellow oil. ¹H NMR(CDCl₃) δ 7.42–7.47 (m, 2H), 7.00 (t, 1H), 3.71 (s, 3H), 3.63 (s, 2H).

Part G. To methyl (2-fluoro-4-iodophenyl)acetate (1.0 g, 3.4 mmol) indimethylsulfoxide (68 mL) was added potassium carbonate (1.9 g, 14 mmol)and 2-hydroxypyridine (650 mg, 6.8 mmol). The resulting mixture wasdegassed (alternate vacuum/nitrogen three times), and copper(I) iodide(650 mg, 3.4 mmol) was added in one portion. The light green mixture wasagain degassed (vac/N₂) and warmed to 125° C. After 14 h, thebrown-black mixture was cooled and poured into saturated aqueousammonium hydroxide (50 mL) and ethyl acetate (100 mL). The layers wereseparated, and the organic layers were washed with water (2×50 mL) andsaturated aqueous sodium chloride. The organic layers were concentrated,and the resulting residue was purified by radial chromatography (20–100%ethyl acetate in hexanes) to afford methyl[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetate (340 mg, 39%) as agreen-brown solid. LC/MS (ESI⁺): 262.2 (M+H)⁺. ¹H NMR (CDCl₃) δ7.22–7.36 (m, 3H), 7.08 (t, 2H), 6.54 (d, 1H), 6.18 (t, 1H), 3.63 (s,5H).

Part H. To a stirring solution of trimethylacetyl chloride (0.026 mL,0.21 mmol), triethylamine (0.058 mL, 0.42 mmol), and diethyl ether (2.6mL) in a flame-dried flask was added1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(60 mg, 0.21 mmol). The resulting white slurry was warmed to 23° C. andstirred for 1.5 h. The mixture was filtered, and the filtrate wasconcentrated. The resulting residue was partially redissolved in diethylether (2 mL) and filtered again. The filtrate was concentrated to give2,2-dimethylpropanoic1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicanhydride as a viscous oil.

In a separate flame-dried flask was combined tetrahydrofuran (0.80 mL),hexamethylphosphoramide (0.80 mL), and diisopropylamine (0.050 mL, 0.36mmol). The solution was cooled to −78° C., and n-butyllithium (0.176 mL,0.44 m mmol) was added in one portion. After 20 min, methyl(2-fluoro-4-iodophenyl)acetate (110 mg, 0.42 mmol; Part F) intetrahydrofuran (1.0 mL) was added via cannula, and the resulting redmixture was maintained at −78° C. for 20 min. The previously prepared2,2-dimethylpropanoic1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicanhydride was then added via cannula as a solution in tetrahydrofuran(1.5 mL), and the resulting light yellow mixture was warmed to 23° C.After 2 h, the reaction was poured into 1N aqueous hydrochloric acid (50mL), washed with ethyl acetate (3×50 mL), and the organic layers werewashed with saturated aqueous sodium chloride, dried over sodiumsulfate, and concentrated. The resulting residue was purified by radialchromatography (1–5% methyl alcohol in dichloromethane) to afford methyl2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-oxopropanoate(54 mg, 49%) as a white solid. LC/MS (ESI⁺): 530.1 (M+H)⁺.

Example 721-(3-fluoro-4-{2-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-oxoethyl}phenyl)-2(1H)-pyridinone

Part A. To methyl2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-oxopropanoate(Part H, Example 71) (24 mg, 0.045 mmol) was added methyl alcohol (2.3mL) and concentrated aqueous dihydrogen sulfate (0.048 mL).

The reaction was then warmed to reflux. After 48 h, monitoring by LC/MS(C18 reverse phase, eluted with 0.05% TFA in acetonitrile/water) showed90% of starting material remaining. An additional 0.80 mL-portion of 4Maqueous dihydrogen sulfate was added, and the reaction was maintainedunder reflux conditions for 6 h. The reaction was cooled to 0° C., andthe resulting white precipitate was filtered to afford1-(3-fluoro-4-{2-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-oxoethyl}phenyl)-2(1H)-pyridinone(11 mg, 52%) as a white solid. LC/MS (ESI⁺): 472.1 (M+H)⁺. ¹H NMR (enolform) (CD₃OD) δ 7.70 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.28 (m, 3H),7.20 (m, 1H), 6.98 (m, 2H), 6.62 (d, 1H), 6.44 (t, 1H), 4.42 (s 0.5H),4.39 (br s, 0.5H), 3.81 (s, 3H).

Example 731-(4-{2-[1-(3-amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-oxoethyl}-3-fluorophenyl)-2(1H)-pyridinonetrifluoroacetate

Part A. To a stirring solution of trimethylacetyl chloride (0.021 mL,0.17 mmol), triethylamine (0.071 mL, 0.51 mmol), and diethyl ether (3.4mL) in a flame-dried flask was added1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (51 mg, 0.17 mmol). The resulting white slurry was warmed to 23° C.and stirred for 1.5 h. The mixture was filtered, and the filtrate wasconcentrated. The resulting residue was partially redissolved in diethylether (5 mL) and again filtered. The filtrate was concentrated to give1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic2,2-dimethylpropanoic anhydride.

In a separate flame-dried flask were combined tetrahydrofuran (2.0 mL),hexamethylphosphoramide (1.4 mL) and diisopropylamine (0.052 mL, 0.37mmol). The solution was cooled to −78° C., and n-butyllithium (0.142 mL,0.35 m mmol) was added in one portion. After 20 min, methyl[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)-phenyl]acetate (88 mg, 0.34 mL; PartG, Example 71) was added as a solution in tetrahydrofuran (1.5 mL) viacannula, and the resulting red mixture was maintained at −78° C. for 20min. The previously prepared1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic2,2-dimethylpropanoic anhydride was then added via cannula as a solutionin tetrahydrofuran (1.5 mL), and the resulting light yellow mixture waswarmed to 23° C. After 1 h, the reaction was poured into water (50 mL)and ethyl acetate, and the organic layer was washed with saturatedaqueous sodium chloride, dried over sodium sulfate, and concentrated.The resulting residue was purified by radial chromatography (15–40%ethyl acetate in hexanes) to afford methyl3-[1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-oxopropanoate(22 mg, 23%) as a clear oil. LC/MS (ESI⁺): 543.0 (M+H)⁺.

Part B. To the product from Part A (22 mg, 0.040 mmol) was added methylalcohol (0.72 mL) and 4M aqueous dihydrogen sulfate (0.24 mL). Thereaction was then warmed to reflux. After 24 h, the reaction was cooledto 0° C., and the resulting white precipitate was filtered to afford2-fluoro-5-[5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-3-(trifluoromethyl-1H-pyrazol-1-yl]benzonitrile(12 mg, 61%) as a white solid. LC/MS (ESI⁺): 485.1 (M+H)⁺. ¹H NMR(CDCl₃) δ 7.62–7.71 (m, 2H), 7.46 (s, 1H), 7.35 (m, 1H), 7.33 (m, 3H),7.22 (m, 2H), 6.57 (d, 1H), 6.27 (t, 1H), 4.30 (s, 2H).

Part C. To the product from Part B (10 mg, 0.040 mmol) was addedN,N-dimethylformamide (0.50 mL), water (0.50 mL), and potassiumcarbonate (29 mg, 0.20 mmol). Acetohydroxamic acid (3.5 mg, 0.046 mmol)was added in one portion, and the resulting yellow mixture was warmed to50° C. After 2 h, the reaction was cooled to rt and the reaction mixturewas purified by preparative LC/MS (C18 reverse phase, eluted with 0.05%TFA in CH₃CN/H₂O) to give1-(4-{2-[1-(3-amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-oxoethyl}-3-fluorophenyl)-2(1H)-pyridinonetrifluoroacetate (8.0 mg, 67%) as a beige solid. LC/MS (ESI⁺): 498.0(M+H−TFA)⁺. ¹H NMR (CD₃OD) δ 7.83(d, 1H), 7.80 (s, 1H), 7.52–7.62 (m,3H), 7.40–7.48 (m, 2H), 7.16–7.26 (m, 2H), 6.60 (d, 1H), 6.40 (t, 1H),4.46 (s, 2H).

Example 745-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide

Part A. A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solutionwas cooled to −78° C. and 2-acetylfuran (14 g, 12 m mmol) was added inone portion. After 5 min, di-tert-butyl oxalate was added dropwise over1 h as a solution in 100 mL of ether. The resulting mixture was warmedto 23° C. over a period of 3 h and was maintained at rt for 20 h. Themixture was then filtered, and the resulting beige precipitate waswashed with 100 mL of ether. The filter cake was dried in a vacuum ovenfor 1 h to afford lithium1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (25 g, 83%) as acream colored solid. ¹H NMR (DMSO-d₆) δ 7.75 (t, 1H), 6.96 (m, 1H), 6.56(m, 1H), 3.34 (s, 2H), 1.46 (s, 9H).

Part B. To the product (1.0 g, 4.6 mmol) from Part A was added4-methoxyphenylhydrazine hydrochloride (480 mg, 2.8 mmol) and glacialacetic acid (15 mL). The resulting orange mixture was warmed to 40° C.and was then cooled to rt after 1.5 h. The reaction was poured intosaturated aqueous sodium bicarbonate (100 mL), and the aqueous layer waswashed with ethyl acetate (3×50 mL). The combined organic layers werewashed with saturated aqueous sodium chloride, dried over sodiumsulfate, and concentrated to dryness. The resulting red-black residuewas recrystallized from hexanes to afford tert-butyl5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (870 mg, 93%)as a yellow-orange solid. ¹H NMR (CDCl₃) δ 7.40(br s, 1H), 7.35 (d, 2H),7.07 (s, 1H), 6.96 (d, 2H), 6.30 (m, 1H), 5.86 (d, 9H), 3.86 (s, 3H),1.62 (s, 9H).

Part C. To tert-butyl5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.0 g, 3.0mmol) was added dichloromethane (7 mL) and trifluoroacetic acid (7 mL).The resulting black solution was maintained at rt under nitrogen for 2 hand was then concentrated to dryness. The resulting mixture wastriturated with chloroform, and the remaining solid was washed with 50%hexanes in chloroform to afford5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (800 mg,96%) as a light brown solid. ¹H NMR (d₆-DMSO) δ 7.75 (b m, 1H), 7.41 (d,2H), 7.10 (d, 2H), 7.09 (s, 1H), 6.51 (br m, 1H), 6.09 (d, 1H), 3.84 (s,3H).

Part D. To the product (800 mg, 2.8 mmol) from Part C was addeddichloromethane (50 mL) and 2.0 M oxalyl chloride (2.1 mL, 4.2 mmol) indichloromethane. After dropwise addition of N,N-dimethylformamide (2drops) to the brown mixture, gas evolved and the mixture became clearover a period of 30 min. The brown solution was concentrated; theresulting residue was redissolved in dichloromethane (50 mL), and 0.5 Mammonia in dioxane (23 mL, 11 mmol) was added via cannula. After 30 min,the resulting beige suspension was poured into water (80 mL). Theaqueous layer was washed with dichloromethane (3×50 mL), and thecombined organic layers were dried over sodium sulfate and concentratedto afford 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide (650mg, 82%) as a beige solid. LC/MS (ESI⁺): 284.1 (M+H)⁺. ¹H NMR (CD₃OD) δ7.52(s, 1H), 7.35 (d, 2H), 7.07 (s, 1H), 7.05 (d, 2H), 6.39 (br m, 1H),5.96 (d, 1H), 4.88 (s, 3H).

Part E. To 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide(2.0 g, 6.6 mmol) was added pyridine (1.6 mL, 20 mmol) and dioxane (66mL). Trifluoroacetic anhydride (1.9 mL, 13 mmol) was added dropwise over2 min, and the resulting suspension was stirred for 40 min. The nowclear red solution was poured into water (70 mL) and ethyl acetate (70mL). The layers were separated, and the organic layer was washed with 1Naqueous hydrochloric acid (2×50 mL), saturated aqueous sodium chloride,and dried over sodium sulfate. The organic layers were concentrated, andthe resulting residue was purified by radial chromatography (20–80%ethyl acetate in hexanes) to afford5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile (1.4 g, 74%)as an orange solid. LC/MS (ESI⁺): 266.0 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.44(br m, 1H), 7.34 (d, 2H), 7.01 (s, 1H), 7.00 (d, 2H), 6.34 (m, 1H), 5.92(d, 1H), 3.85(s, 3H).

Part F. To the product (1.4 g, 4.9 mmol) from Part E was added water (30mL), 5% aqueous sodium dihydrogenphosphate (21 mL), and tert-butanol (30mL). The resulting mixture was warmed to 60° C., and potassiumpermanganate (4.7 g, 29 mmol) was added over a period of 5 min. After anadditional 5 min, the resulting purple slurry was cooled to 0° C., andthe reaction was quenched by the addition of 50 mL of saturated aqueoussodium bisulfite. The resulting brown mixture was filtered, washed with100 mL of water, and the filtrate was acidified with 6N aqueous hydrogenchloride. The resulting mixture was filtered to afford3-cyano-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (300 mg, 25%)as a yellow solid. Extraction of the aqueous layer with ethyl acetate(2×50 mL) afforded an additional 215 mg (18%) of impure3-cyano-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid as a yellowoil. LC/MS (ESI⁺): 244.1 (M+H)⁺. ¹H NMR (precipitate) (CDCl₃) δ 7.42 (s,1H), 7.35 (d, 2H), 6.98 (d, 2H), 3.87 (s, 3H).

Part G. To a stirring solution of trimethylacetyl chloride (0.087 mL,0.70 mmol), triethylamine (0.290 mL, 2.1 mmol), and diethyl ether (14mL) in a flame-dried flask was added3-cyano-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (170 mg, 0.70mmol). The resulting white slurry was warmed to 23° C. and stirred for1.5 h. The mixture was filtered, and the filtrate was concentrated. Theresulting residue was partially redissolved in diethyl ether (15 mL) andagain filtered. The filtrate was concentrated to give3-cyano-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic2,2-dimethylpropanoic anhydride as a viscous oil.

In a separate flame-dried flask were combined tetrahydrofuran (8.0 mL),hexamethylphosphoramide (6.0 mL), and diisopropylamine (0.200 mL, 1.5mmol). The solution was cooled to −78° C., and n-butyllithium (0.560 mL,1.4 m mmol) was added in one portion. After 20 min,[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)-phenyl]acetate (360 mg, 1.4 mL; PartG, Example 71) in tetrahydrofuran (5 mL) was added via cannula, and theresulting red mixture was maintained at −78° C. for 20 min. Thepreviously prepared 3-cyano-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic2,2-dimethyl-propanoic anhydride was then added via cannula as asolution in tetrahydrofuran (5 mL), and the resulting light yellowmixture was warmed to 23° C. After 12 h, the reaction was poured intowater (50 mL) and ethyl acetate (75 mL), and the organic layer waswashed with saturated aqueous sodium chloride, dried over sodiumsulfate, and concentrated. The resulting residue was purified by radialchromatography (50–60% ethyl acetate in hexanes) to afford3-[3-cyano-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-oxopropanoate(131 mg, 40%) as a foamy solid. LC/MS (ESI⁺): 487.0 (M+H)⁺.

Part H. To3-[3-cyano-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-oxopropanoate(100 mg, 0.210 mmol) was added methyl alcohol (1.5 mL) and 4M aqueousdihydrogen sulfate (0.50 mL). The reaction was then warmed to reflux.After 4 days, the reaction was cooled to 23° C., and the resulting whitesuspension was poured into saturated aqueous hydrogen carbonate (50 mL)and ethyl acetate (50 mL). The layers were separated and the aqueouslayer was washed with ethyl acetate (3×25 mL). The combined organiclayers were washed with saturated aqueous sodium chloride, dried oversodium sulfate, and concentrated to afford5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile(75 mg, 85%) as a pale yellow oil. LC/MS (ESI⁺): 429.0 (M+H)⁺.

Part I. To5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile(75 mg, 0.175 mmol) was added concentrated aqueous dihydrogen sulfate(4.5 mL). After 2 h, the reaction was poured into ethyl acetate (50 mL)and water (50 mL), and the layers were separated. The organic layer waswashed with saturated aqueous sodium chloride (50 mL), dried over sodiumsulfate, and concentrated to dryness. The resulting residue was purifiedby radial chromatography (2% methyl alcohol in dichloromethane) toafford5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide(32 mg, 41%) as a white solid upon lyopholization from 10% acetonitrilein water. LC/MS (ESI⁺): 448.2 (M+H)⁺. ¹H NMR (CD₃OD) δ 7.70 (s, 1H),7.60 (m, 2H), 7.43 (t, 1H), 7.16–7.32 (m, 4H), 6.97 (d, 2H), 6.60 (d,1H), 6.45 (t, 1H), 4.40 (s, 2H), 3.83 (s, 3H).

Example 751-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxo-1(2H)pyridinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide

Part A. To lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate(13 g, 54 mmol; Example 74, Part A) was added2-fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250mL of glacial acetic acid. The resulting orange mixture was maintainedat rt for 20 h and then concentrated to dryness. The resulting residuewas taken up in 30% chloroform in hexanes and filtered to affordtert-butyl1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate (18 g,95%) as a light brown solid. LC/MS (ESI⁺): 354.2 (M+H)⁺. ¹H NMR (CDCl₃)δ 7.64–7.78(m, 3H), 7.42 (s, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 6.30 (s,1H), 1.61 (s, 9H).

Part B. To the product from Part A (10 g, 28 mmol) was added 125 mL ofdichloromethane and 125 mL of trifluoroacetic acid. The resulting blacksolution was maintained at rt under nitrogen for 2 h and was thenconcentrated to dryness. The resulting solid was triturated with ethylacetate and then dried in a vacuum oven for 4 h to afford1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylic acid(5.3 g, 63%) as a light brown solid. LC/MS (ESI⁺): 298.1 (M+H)⁺. ¹H NMR(CD₃OD) δ 7.90(m, 1H), 7.75 (m, 1H), 7.51 (s, 1H), 7.46 (t, 1H), 6.98(s, 1H), 6.47 (m, 1H), 6.35 (m, 1H).

Part C. To the product (4.1 g, 14 mmol) from Part B was added 23 mL ofdichloromethane and 2.0 M oxalyl chloride (10 mL, 21 mmol) indichloromethane. After dropwise addition of N,N-dimethylformamide (10drops), the brown mixture became a clear solution over a period of 30min. The solution was concentrated; the resulting residue wasredissolved in 100 mL of dichloromethane, and 0.5 M ammonia in dioxane(110 mL, 55 mmol) was added via cannula. After 30 min, the resultingsuspension was concentrated and poured into water. The aqueous layer waswashed with ethyl acetate (3×70 mL), and the combined organic layerswere washed with saturated aqueous sodium chloride, dried over sodiumsulfate, and concentrated. The resulting residue was dissolved in 10 mLof dichloromethane and 50 mL of hexanes were added. The resultingsuspension was filtered, and the filter cake was washed with 50 mL ofhexanes, and dried in a vacuum oven to afford1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxamide (2.5 g,62%) as a brown solid. LC/MS (ESI⁺): 297.1 (M+H)⁺. ¹H NMR (CDCl₃) δ7.75(m, 1H), 7.64 (m, 1H), 7.42 (s, 1H), 7.33 (t, 1H), 7.16 (s, 1H),6.79 (br s, 1H), 6.46(m, 1H), 6.36 (m, 1H), 5.50 (br s, 1H).

Part D. To the product (2.5 g, 8.3 mmol) from Part C was added water (51mL), 5% aqueous sodium dihydrogenphosphate (35 mL), and tert-butanol (51mL). The resulting mixture was warmed to 60° C., and potassiumpermanganate (8.0 g, 51 mmol) was added over a period of 10 min. Afteran additional 10 min, the resulting purple slurry was cooled to 0° C.,and the reaction was quenched by the addition of 200 mL of saturatedaqueous sodium bisulfite. The resulting mixture was filtered, washedwith 300 mL of water, and the filtrate was acidified with concentratedhydrogen chloride. The aqueous layer was extracted with ethyl acetate(6×10 mL) and the combined organic layers were washed with saturatedaqueous sodium chloride, dried over sodium sulfate, and filtered.Concentration afforded3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylicacid (1.6 g, 71%) as a yellow solid. LC/MS (ESI⁺): 275.1 (M+H)⁺. ¹H NMR(CD₃OD) δ 8.03 (m, 1H), 7.90 (m, 1H), 7.5 (t, 1H), 7.44 (s, 1H).

Part E. Sodium cyanoborohydride (1.54 g, 25 mmol) was added in oneportion to a stirring orange solution of 5-iodo-1H-indole (6.0 g, 25mmol) in glacial acetic acid (350 mL). After 24 h, the orange solutionwas concentrated. To the resulting red residue was added tetrahydrofuran(250 mL) and di-tert-butyl dicarbonate (16 g, 74 mmol) followed bysaturated aqueous sodium bicarbonate (20 mL). The resulting mixture wasstirred for 24 h and was then poured into aqueous 1N hydrogen chloride(70 mL). The layers were separated, and the aqueous layer was washedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith saturated aqueous sodium chloride (50 mL), dried over sodiumsulfate and concentrated. The resulting residue was dissolved in THF(100 mL), and benzyl amine (6 mL, 55 mol) was added. The resultingsolution was stirred for 1.5 h and was then poured into 1N hydrogenchloride (70 mL). The layers were separated and the aqueous layer waswashed with ethyl acetate (3×50 mL). The combined organic layers werewashed with saturated aqueous sodium chloride (50 mL), dried over sodiumsulfate, and concentrated. Purification of the resulting residue byflash column chromatography (5% ethyl acetate in hexanes) affordedtert-butyl 5-iodo-1-indolinecarboxylate (3.9 g, 45%) as a white solid.LC/MS (ESI⁺): 346.1 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.43 (m, 1H), 7.15 (m, 1H),6.89 (dt, 1H), 3.96 (m, 2H), 3.08 (t, 1H), 3.05 (t, 1H) 1H), 1.55 (s,9H).

Part F. To the product (1.65 g, 4.8 mmol) from Part E was addeddimethylsulfoxide (59 mL), 2-hydroxypyridine (910 mg, 9.6 mmol), andpotassium carbonate (2.6 g, 19 mmol). The resulting mixture was degassed(alternate vacuum & nitrogen; three times), and copper(I) iodide (910mg, 4.8 mmol) was added in one portion. The now light green mixture wasagain degassed (vac/N₂) and warmed to 122° C. After 3 h, the mixture wascooled and poured into saturated aqueous ammonium hydroxide (100 mL) andethyl acetate (200 mL). The layers were separated, and the aqueous layerwas washed with one 50 mL-portion of ethyl acetate. The combined organiclayers were then washed with water (2×50 mL), saturated aqueous sodiumchloride, and dried over sodium sulfate. The organic layers wereconcentrated, and the resulting oil was purified by flash columnchromatography (10–100% ethyl acetate in hexanes) to afford tert-butyl5-(2-oxo-1(2H)-pyridinyl)-1-indolinecarboxylate (660 mg, 44%) as ayellow solid. LC/MS (ESI⁺): 313.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.41 (dd,1H), 7.34 (dd, 1H), 7.25 (s, 1H), 7.18 (d, 1H), 6.73 (d, 1H), 6.23 (t,1H), 4.08 (br s, 2H), 3.16 (t, 2H), 1.68 (s, 9H).

Part G. To the product (610 mg, 2.0 mmol) from Part F was addeddichloromethane (6 mL) and trifluoroacetic acid (6 mL). After 20 min,the reaction was concentrated to dryness and treated with saturatedaqueous sodium bicarbonate (15 mL). The layers were separated, and theaqueous layer was washed with dichloromethane (2×50 mL). The organiclayers were dried over sodium sulfate and concentrated to afford1-(2,3-dihydro-1H-indol-5-yl)-2(1H)-pyridinone (410 mg, 99%). LC/MS(ESI⁺): 213.1 (M+H)⁺. ¹H NMR (CDCl₃) δ 7.55–8.09 (br m, 1H), 7.30–7.40(m, 2H), 7.14 (s, 1H), 6.95 (d, 1H), 6.66 (d, 1H), 6.64 (d, 1H), 6.19(dt, 1H), 3.62 (t, 2H), 3.08 (t, 2H).

Part H. To the product from Part G (274 mg, 1.30 mmol) was added3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylicacid (390 mg, 1.4 mmol), followed by pyridine (11 mL) andN,N-dimethylformamide (4.0 mL). Then 1,3-diisopropylcarbodiimide (0.242mL, 1.6 mmol) was added, and the resulting solution was stirred for 14h. The red mixture was poured into 1N aqueous hydrochloric acid (70 mL)and washed with ethyl acetate (60 mL). The organic layer was washed with1N aqueous hydrochloric acid (3×25 mL), saturated aqueous sodiumchloride, and dried over sodium sulfate. Concentration of the organiclayers and purification of the resulting residue by radialchromatography (5% methyl alcohol in dichloromethane) afforded partiallypure1-(3-cyano-4-fluorophenyl)-5-{[5-(2-oxo-1(2H)-pyridinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide(620 mg, 62%) as a red oil (LC/MS (ESI⁺): 469.0 (M+H)⁺). This materialwas dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate(910 mg, 6.6 mmol) and water (3.0 mL) were added. Acetohydroxamic acid(110 mg, 1.5 mmol) was added in one portion, and the resulting yellowmixture was warmed to 50° C. After 1.5 h, the reaction was cooled to rt,concentrated, and diluted with ethyl acetate (10 mL). Filtrationafforded1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[5-(2-oxo-1(2H)-pyridinyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide(100 mg, 16%) as a white solid. LC/MS (ESI⁺): 482.1 (M+H)⁺. ¹H NMR(d₆-DMSO) δ 8.09(s, 1H), 8.01 (d, 1H), 7.85 (s, 1H), 7.68 (m, 1H),7.46–7.62 (m, 3H), 7.38 (d, 2H), 7.18 (br d, 1H), 6.58 (s, 1H), 6.46 (d,1H), 6.29 (t, 1H), 4.34 (br t, 2H), 3.22 (br t, 2H).

Example 761-(2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

Part A. 1-benzyl-6-indolinamine (2.40 g, 10.85 mmol) was stirred inconc. HCl (25 mL) at 0° C. under N₂. A pre-cooled solution of NaNO₂(0.749 g, 10.85 mmol) in H₂O (2 mL) was added dropwise and slowly. Themixture was then stirred at 0° C. for 40 min after the addition. Asolution of SnCl₂.2H₂O (6.10 g, 2.5 eq) in conc. HCl (7 mL) was addedslowly to the stirred solution at 0° C. The resulting mixture wasstirred vigorously at 0° C. for 30 min. A slurry of the1-(4-Iodophenyl)-4-(2,2,2-trifluoroacetyl)-piperidine-2,3-trione (4.20g, 1.02 mmol) in MeOH (30 mL) was added portionwise to the mixture at 0°C. The resulting mixture was gradually warmed up and stirred at RT for 2h, then 50° C. for 5 h. LC-MS showed completion of the reaction. Thesolvents were evaporated. The residue was basified with aqueous NaOH;extracted with EtOAc; washed with H₂O, brine, dried over MgSO₄, andconcentrated. The residue was purified by flash column chromatography(silica gel, CH₂Cl₂) to produce light orange-yellow crystals of1-(1-benzyl-2,3-dihydro-1H-indol-6-yl)-6-(4-iodophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(2.05 g, 31%). ¹H NMR (CDCl₃) δ 7.69 (dd, J=8.5, 1.9 Hz, 2H), 7.34–7.25(m, 6H), 7.08 (dd, J=6.9, 2.2 Hz, 2H), 6.76 (dd, J=7.7, 1.8 Hz, 1H),6.58 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 4.10 (t, J=6.6 Hz, 2H), 3.35 (t,J=8.4 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H), 2.97 (t, J=8.4 Hz, 2H). ¹³C NMR(CDCl₃) δ 156.4, 152.9, 141.4, 138.8, 137.9, 137.8, 132.9, 131.3, 128.6,127.9, 127.3, 127.2, 124.0, 122.0, 115.0, 104.0, 91.0, 53.6, 53.1, 50.6,28.3, 20.4, 14. ¹⁹F NMR (CDCl₃) δ-61.4. LC-MS (ESI) 615.2(M+H).

Part B. The product from Part A (0.33 g, 0.54 mmol), 2-hydroxypyridine(0.13 g, 1.37 mmol), and K₂CO₃ (0.20 g, 1.45 mmol) were stirred in DMSO(1.5 mL) at RT under N₂. CuI (44 mg, 0.23 mmol) and 1,10-phenanthroline(40 mg, 0.23 mmol) were added. The resulting mixture was stirred at 140°C. for 2.5h under N₂. LC-MS showed disappearance of the startingmaterial from Part A. The mixture was cooled to RT, and EtOAc was added.It was washed with H₂O, brine, dried over MgSO₄, and concentrated. Thecrude compound of1-(1-benzyl-2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-onewas used directly in the next step. ¹H NMR (CDCl₃) δ 7.50–1.22 (m, 9H),7.09 (d, J=8.4 Hz, 2H), 6.85 (dd, J=7.2, 1.2 Hz, 1H), 6.78 (d, J=8.4 Hz,1H), 6.71 (d, J=1.2 Hz, 1H), 6.37 (td, J=7.2, 1.2 Hz, 1H), 4.29 (s, 2H),4.19 (t, J=6.3 Hz, 2H), 3.39 (t, J=8.4 Hz, 2H), 3.17 (t, J=6.3 Hz, 2H),2.96 (t, J=8.5 Hz, 2H). LC-MS (ESI) 582.2 (M+H).

Part C. The product from Part B (0.33 g, 0.57 mmol), NaI (0.17 g, 1.14mmol), and 1-chloroethyl chloroformate (0.10 mL, 1.8 eq) were stirred inacetone (2 mL) for 1.5 h at RT under N₂. The solvent was evaporated, andthe residue was dissolved in MeOH (4 mL). It was refluxed for 1 h. Theresidue was purified by prep LC-MS (5–98% CH₃CN in H₂O, t_(R)=4.18 minin a 10-min run). The fractions were collected and lyophilized to give1-(2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.¹H NMR (CD₃COCD₃) δ 7.56–7.41 (m, 6H), 7.07 (d, J=7.8 Hz, 1H), 6.78–6.72(m, 2H), 6.45 (d, J=8.8 Hz, 1H), 6.28 (td, J=7.0, 1.5 Hz, 1H), 4.25 (t,J=6.6 Hz, 2H), 3.55 (t, J=8.1 Hz, 2H), 3.17 (t, J=6.6 Hz, 2H), 2.98 (t,J=8.1 Hz, 2H). LC-MS (ESI) 492.4 (M+H).

Example 771-(2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one,trifluroacetic acid salt

Part A. The product from Part A of Example 71 (0.89 g, 1.45 mmol),δ-valerolactam (0.20 g, 2.02 mmol), and K₂CO₃ (0.41 g, 2.97 mmol) werestirred in DMSO (5 mL) at RT under N₂. CuI (86 mg, 0.45 mmol) and1,10-phenanthroline (80 mg, 0.43 mmol) were added. The resulting mixturewas stirred at 130° C. overnight under N₂. The mixture was cooled to rt,and EtOAc was added. It was washed with brine (2×), dried over MgSO₄,and concentrated. The residue was purified by flash columnchromatography (silica gel, CH₂Cl₂, then CH₂Cl₂:EtOAc=10:3) to producethe desired product1-(1-benzyl-2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(0.51 g, 68% based on recovered starting material). ¹H NMR (CDCl₃) δ7.36–7.22 (m, 8H), 7.06 (d, J=7.7 Hz, 1H), 6.76 (dd, J=7.7, 1.8 Hz, 1H),6.59 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 4.12 (m, 2H), 3.59 (m, 2H), 3.34(t, J=8.4 Hz, 2H), 3.12 (t, J=6.6 Hz, 2H), 2.96 (t, J=8.4 Hz, 2H), 2.56(m, 2H), 1.93 (m, 4H). LC-MS (ESI) 586.4 (M+H).

Part B. The product from Part A (0.51 g, 0.87 mmol), NaI (0.26 g, 1.74mmol), and 2-chloroethyl chloroformate (0.16 mL, 1.8 eq) were stirred inacetone (5 mL) for 4 h at RT under N₂. The solvent was evaporated; andthe residue was purified by flash column chromatography (silica gel,CH₂Cl₂, then EtOAc, then EtOAc:MeOH=10:1) to give the intermediatecarbamate. The fractions were concentrated, and dried under vacuum for10 min. It was dissolved in MeOH (30 mL), and refluxed under N₂ for 1 h.The residue was purified by prep LC-MS (35–98% CH₃CN in H₂O, t_(R)=2.24min in a 10-min run). The fractions were collected and lyophilized toyield1-(2,3-dihydro-1H-indol-6-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-oneas white solids. ¹H NMR (CD₃COCD₃) δ 7.33 (AA′BB′, J=9 Hz, 4H), 6.82 (d,J=7.7 Hz, 1H), 6.79 (m, 2H), 4.68 (t, J=6.6 Hz, 2H), 3.67 (t, J=6.6 Hz,2H), 3.58 (t, J=8.4 Hz, 2H), 3.16 (t, J=6.6 Hz, 2H), 3.00 (t, J=8.1 Hz),2.40 (t, J=6.1 Hz, 2H), 1.91 (m, 4H). LC-MS (ESI) 496.4 (M+H).

Example 781-(2,3-Dihydro-1H-isoindol-5-yl)-6-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt

Part A. A solution of 4-nitro-o-xylene (38.64 g, 255.9 mmol), NBS (91.1g, 511.8 mmol), benzoyl peroxide (1.239 g, 5.118 mmol), and CCl₄ (400mL) was heated at reflux for 1 day, then at rt for 2 days. The solid wasfiltered off and washed with CCl₄. The filtrate was evaporated to givethe crude dibromo product (80 g). A portion of which (20 g) wasdissolved in acetone (170 mL) and water (45 mL), then Na₂CO₃ (43.1 g,407 mmol) was slowly added, followed by BnNH₂ (7.05 mL, 64.6 mmol) inacetone (22 mL). After 10 h, the solution was concentrated to one-fourthits volume, the salt solid was filtered off, and the filtrate wasevaporated. The residue was dissolved in EtOAc, washed with water andbrine, dried over sodium sulfate, filtered, and evaporated. The residuewas purified by column chromatography to provide the corresponding2-benzyl-5-nitro-2,3-dihydro-1H-isoindole (5.41 g, 33% yield, over 2steps): ¹H NMR (300 MHz, CDCl₃) δ 8.11 (d, 1H), 8.04 (s, 1H), 7.48–7.20(m, 6H), 4.02 (s, 4H), 3.92 (s, 2H).

Part B. To a solution of the isoindoline (5.40 g, 21.3 mmol) made abovein EtOH (266 mL) under N₂ was added 20% Pd(OH)₂/C (3.00 g, 4.25 mmol).The reaction mixture was hydrogenated at 45 psi for 1 h. TLC analysisindicated that the nitro functionality was reduced and the Bn group wasstill intact. Therefore, concentrated HCl (1.6 mL, 19.1 mmol) was addedto the reaction mixture and hydrogenation (50 psi) was continuedovernight. The mixture was filtered through Celite®, washed with MeOH,and the filtrate was concentrated to one fourth of the volume. Theprecipitate was filtered off to provide the 5-aminoisoindoline.HCl (1.32g, 36% yield): ¹H NMR (500 MHz, CDCl₃) δ 9.88 (s, br, 2H), 7.00 (d, 1H),6.54 (m, 2H), 5.44 (s, br, 2H), 4.32 (s, 2H), 4.28 (s, 2H); ESI MS m/z135 (M-HCl+H)⁺.

Part C. The 5-aminoisoindoline (700 mg, 4.11 mmol) made above wasdissolved in 6 M HCl (4.6 mL) at rt, then cooled to 0° C. A solution ofNaNO₂ (340 mg, 4.93 mmol) in water (0.8 mL) was added dropwise,maintaining the reaction temperature below 5° C. After 40 min, AcOH (1.4mL) was added to the mixture, followed by the dropwise addition of SnCl₂(1.79 g, 9.44 mmol) in concentrated HCl (2.7 mL) at 0° C. The mixturewas warmed to 10° C. and stirred for 2 h, then a solution of3-hydroxy-1-(4-iodophenyl)-4-(2,2,2-trifluoroacetyl)-5,6-dihydro-1H-pyridin-2-one(1.78 g, 4.31 mmol) in MeOH (16 mL) was added and the reaction mixturewas heated at 50° C. for 16 h. Methyl alcohol was removed under vacuumand the solid was collected by filtration to give1-(2,3-dihydro-1H-isoindol-5-yl)-6-methyl-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;compound with iodo-benzene as an AcOH salt (2.07 g, 86% yield): ¹H NMR(500 MHz, DMSO-d₆) δ 9.82 (s, br, 2H), 7.75 (d, 2H), 7.66–7.62 (m, 2H),7.51 (d, 1H), 7.19 (d, 2H), 4.56 (m, 4H), 4.11 (t, 2H), 3.12 (t, 2H);ESI MS m/z 585 (M+H)⁺.

Part D. The product from Part C (540 mg, 1.03 mmol) was added to astirred solution of Et₃N (143 mL, 1.03 mmol) and Boc₂O (225 mg, 1.03mmol) in THF (5.2 mL) at rt. After 2.5 h, the solvent was removed undervacuum and the residue was purified by column chromatography to providethe corresponding protected isoindoline5-(6-methyl-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester; compound with iodo-benzene (272 mg, 42% yield):¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, 2H), 7.45–7.26 (m, 3H), 7.06 (d, 2H),4.68 (m, 4H), 4.13 (t, 2H), 3.17 (t, 2H), 1.51 (s, 9H); ¹⁹F NMR (282MHz, CDCl₃) δ-61.8.

Part E. A mixture of the product from Part D (102 mg, 163 μmol),2-hydroxy-pyridine (19 mg, 196 μmol), K₂CO₃ (25 mg, 180 μmol), 1,10-phenanthroline (3 mg, 18 mmol), CuI (4 mg, 20 μmol, and DMSO (0.3 mL)under argon atmosphere was heated at 110–120° C. for 24 h. The mixturewas diluted with CH₂Cl₂, washed 1 M HCl (2×) and brine, dried oversodium sulfate, filtered, and evaporated under vacuum. The residue waspurified by column chromatography to provide the corresponding biaryllactam (17 mg), which was treated with TFA (21 mL) to provide, afterpurification by semi-preparative HPLC, the title compound1-(2,3-dihydro-1H-isoindol-5-yl)-6-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one,trifluoroacetic acid salt (3.8 mg, 4% yield, 3 steps): ¹H NMR (300 MHz,CDCl₃) δ 9.77 (s, br, 2H), 7.63–7.34 (m, 8H), 7.10 (d, 1H), 6.69 (d,1H), 6.45 (t, 1H), 4.21 (t, 2H), 4.07 (s, 2H), 3.20 (t, 2H), 1.31 (m,2H); ¹⁹F NMR (282 MHz, CDCl₃) δ-62.0, -76.2; ESI MS m/z 492(M−CF₃CO₂H+H)⁺.

Example 791-(4-Methoxyphenyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-3-(2-pyrrolidin-1-ylmethyl-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

Part A. A 250 mL flask containing a stir bar was charged with4-methoxyphenylhydrazine HCl (3 g, 17 mmol) and 25 mL water. A solutionof glyoxylic acid monohydrate (1.6 g, 17 mmol) dissolved in 15 mL waterwas prepared and added to the stirring solution dropwise via additionfunnel. As the reagent solution was added, the reaction turnedreddish-brown and precipitated while stirring over the course of 3 h atrt. The solid was filtered in a Buchner funnel and washed three timeseach with 1N HCl and water. The hydrazone was isolated as a dark brownsolid (2.7 g, 14 mmol) in 82% yield.

Part B. A 250 mL flask containing a stir bar was charged with hydrazone(1.0 g, 5.1 mmol) from part A and 10 mL DMF, then cooled to 0° C. Thesystem was flushed with N₂. A solution of N-bromosuccinimide (1.8 g, 10mmol) in 2 mL DMF was also prepared and added to the reaction flaskdropwise by syringe. Gas evolution was evident as the reagent was added.The reaction stirred for 15 min at 0° C. Iodo-morpholine enamine (3 g,7.7 mmol) and a solution of triethylamine (1.4 mL, 10 mmol) in 20 mLtoluene were added to the reaction at 0° C. The reaction stirredovernight while warming to rt. The solution was diluted by the additionof water and ethyl acetate and transferred to an addition funnel. Theaqueous phase was separated and extracted three times with ethylacetate. The organics were combined and washed with brine before dryingover sodium sulfate. The solvent was removed by rotary evaporation toyield the morpholine intermediate as an orange solid. The crude materialwas purified by flash chromatography (eluent 50% hexane, 50% ethylacetate on silica gel) to afford pure iodo-morpholine intermediate (1.2g, 2.0 mmol) in 38% yield.

Part C. A 100 mL flask with a stir bar was charged with iodo-morpholineintermediate (1.2 g, 2.0 mmol) and 10 mL of methylene chloride beforethe dropwise syringe addition of 1 mL TFA. The system was flushed withN₂ while the reaction stirred overnight at rt. The solution was dilutedwith methylene chloride and saturated sodium bicarbonate before transferto an addition funnel. The aqueous phase was separated and extractedthree times with methylene chloride. The organics were combined andwashed with brine before drying over magnesium sulfate. The solution wasfiltered and solvent was removed by rotary evaporation to yield the3-bromopyrazole as an orange solid. The crude reaction product waspurified by flash chromatography to produce pure 3-bromopyrazole (560mg, 1.1 mmol) in 53% yield.

Part D. An oven-dried 100 mL flask and stir bar were charged with3-bromopyrazole (860 mg, 1.6 mmol), γ-valerolactam (230 mg, 2.5 mmol),potassium carbonate (270 mg, 2.0 mmol), and 10 mL degassed DMF. Copperiodide (62 mg, 0.33 mmol) was added and a reflux condenser was attached.The system was flushed with N₂ while the reaction was heated to 120° C.overnight. The reaction was cooled to rt before dilution with ethylacetate and water. This solution was transferred to an addition funneland the aqueous phase extracted three times with ethyl acetate. Theorganics were combined and washed three times with water and once withbrine before drying over sodium sulfate. The product solution wasfiltered and concentrated to dryness by rotary evaporation. The crudeproduct was purified by flash chromatography to afford the bromo-lactam(150 mg, 0.3 mmol) in 19% yield.

Part E. An oven-dried, 100 mL flask containing a stir bar was chargedwith bromo-lactam (90 mg, 0.18 mmol), 2-formylbenzeneboronic acid, andsodium carbonate (60 mg, 0.54 mmol). The solids were dissolved in 3 mLof a 2:1 mixture of degassed THF and water.Tetrakis-(triphenylphosphine)palladium (10 mg, 0.01 mmol) was addedbefore the flask was fitted with a reflux condenser and the systemflushed with N₂. The reaction was heated to 110° C. while stirringovernight. The reaction was cooled to rt and diluted with water andethyl acetate. The solution was transferred to a separation funnel andthe aqueous phase extracted with ethyl acetate. The organics werecombined and washed with brine before drying over sodium sulfate. Thesolvents were removed by rotary evaporation to afford the desired 3-arylpyrazole (70 mg, 0.13 mmol) in 74% crude yield.

Part F. An oven-dried, 100 mL flask containing a stir bar was chargedwith 3-aryl pyrazole (70 mg, 0.13 mmol) and 30 mL of a 1:1 methylalcohol/THF solution. The system was flushed with N₂ before the syringeaddition of 60 μL of pyrrolidine. The reaction stirred at rt for 15 min.To the reaction solution was added 2M zinc chloride solution in THF (130μL, 0.06 mmol) followed by sodium cyanoborohydride (10 mg, 0.16 mmol).The reaction was stirred at rt while stirring overnight. The reactionwas diluted with ethyl acetate and water. The aqueous phase wasseparated and washed with brine before drying over sodium sulfate. Thesolution was filtered and concentrated in vacuo to afford the crudeproduct. Purification by HPLC followed by freeze-drying produced thedesired amine as a TFA salt. ESI MS m/z 576 (M+H).

Example 805-chloro-N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-piperidine)-1-yl]benzoyl}amino)benzamide

Part A: To a solution of 2-amino-4-chloropyridine (129 mg, 1.0 mmol) inanhydrous THF at −78° C. was added KHMDS (4.0 mL, 0.5 M solution intoluene). The mixture was stirred at this temperature under N₂ for 30min and a solution of 5-chloro-isatoic anhydride (198.0 mg, 1.0 mmol) inTHF was added to the above mixture. The resulted mixture was warmed tort gradually and stirred for 10 h. The reaction mixture was quenchedwith sat. NH₄Cl solution, most of the solvent was evaporated and theresidue was diluted with ethyl acetate, washed with brine, and driedover MgSO₄. Removal of solvent and chromatography on silica gel (20%ethyl acetate in hexane) yielded the desired product2-amino-5-chloro-N-(5-chloro-pyridin-2-yl)-benzamide as light brownsolid. MS found: (M+1)⁺=282.2.

Part B: To a suspension of 4-[(2-oxo-piperidine)-1-yl]benzoic acid (219mg, 1.0 mmol) in CH₂Cl₂ and DMF (0.1 mL) was added oxylyl chloride (2.0mmol). The mixture was stirred for 2 h under N₂. Solvent was removed andthe residue was dried on vacuum to give the acyl chloride. To themixture of part A (124 mg, 0.44 mmol), TEA (0.25 mL) and DAMP (11.0 mg)in CH₂Cl₂ was added a solution of the above acyl chloride in CH₂Cl₂ at0° C. The mixture was warmed to rt and stirred over night under N₂. Themixture was washed with water and purified with reverse phase HPLC (20%CH₃CN/H₂O, 40 mL/min) to provide the desired product as light brownsolid. ESI MS m/z: (M+1)⁺=483.0.

Example 815-chloro-N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)benzamide

Following a procedure analogous to that described in Example 80,5-chloro-N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)benzamidewas obtained as light yellow solid. ESI MS m/z: (M+1)⁺=479.0.

Example 82N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-piperidine)-1-yl]benzoyl}amino)-5-methoxybenzamide

Following a procedure analogous to that described in Example 80, thetitle compound was obtained as light brown solid. ESI MS m/z:(M+1)⁺=479.1.

Example 83N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)-5-methoxybenzamide

Following a procedure analogous to that described in Example 80,N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)-5-methoxybenzamidewas obtained as white solid. ESI MS m/z: (M+1)⁺=475.2.

Example 84N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-piperidin)-1-yl]benzoyl}amino)-5-methylbenzamide

Following a procedure analogous to that described in Example 80, thetitle compound was obtained as white solid. ESI MS m/z: (M+1)⁺=463.2.

Example 85N-(5-chloropyridin-2-yl)-2-({4-[(2-oxo-pyridin)-1-yl]benzoyl}amino)-5-methylbenzamide

Following a procedure analogous to that described in Example 80, thetitle compound was obtained as white solid. ESI MS m/z: (M+1)⁺=459.2.

Example 861-(3-Chloro-phenyl)-3-methanesulfonyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

Part A. 3-Chloroaniline (5.00 g, 39.2 mmol) was added dropwise to anice-cold 1N hydrochloric acid solution followed by the addition of 4 mLof 12M hydrochloric acid. To this solution was slowly added an ice-coldsolution of sodium nitrite (3.00 g, 43.1 mmol) in 4 mL of water whilemaintaining the internal temperature to less than 5° C. This solutionwas stirred for 45 min at 0° C. during which time a precipitate formed.Glacial acetic acid (1 mL) was added and the precipitate dissolved. Tothis solution was added solid sodium acetate (approx. 2 g) to adjust thepH to 4 and then 10 mL ice cold acetone was added followed by an icecold solution of 1-chloro-1-methanesulfonyl-propan-2-one in 10 mLacetone. The reaction was allowed to warm to ambient temperature andstirred for 14 h. A stream of nitrogen was passed over the solution toslightly reduce the solvent volume. The solid precipitate was collectedby filtration, washed twice with water, and dried in vacuo at 40° C. togive 8.47 g (81%) ofN-(3-chlorophenyl)-1-(methylsulfonyl)-methanehydrazonoyl chloride as alight orange solid.

The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. Afterthe addition was complete the reaction was warmed to 90° C. and stirredat this temperature for 14 h. Analysis by LC/MS indicated formation of1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7a-morpholin-4-yl-1,3a,4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-onecomplete with less than 5% of1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-oneremaining. The solvent was removed in vacuo. To the viscous oil wasadded dichloromethane (50 mL) then trifluoroacetic acid (30 mL) andheated to reflux for 4 h. The solvent was evaporated and the residuepurified by flash column chromatography eluting with a gradient ofhexane to 40% ethylacetate/hexane to give 10.65 g (64%) of1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

Part B. In a round bottomed flask were combined1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one(1.00 g, 1.89 mmol), δ-valerolactam (0.36 g, 3.79 mmol), anhydrouspowdered potassium carbonate (1.05 g, 7.58 mmol), cuprous iodide (0.072g, 0.38 mmol), and 1,10-phenanthroline (0.068 g, 0.38 mmol). The flaskwas purge with argon and degassed methylsulfoxide (10 mL) was addedbefore heating to 120° C. Upon completion of the reaction, as judged byTLC or LC/MS, the reaction was cooled to ambient temperature and 50 mLeach of 3M ammonium hydroxide and dichloromethane were added. The phaseswere separated and the aqueous extracted with an additional 30 mL ofdichloromethane. The combined dichloromethane extracts are washedsuccessively four times with water and once with brine. The solution wasdried over sodium sulfate, filtered, and evaporated to give an oil thatwas purified by flash column chromatography eluting with ethylacetate togive 0.424 g (45%) of1-(3-chloro-phenyl)-3-methanesulfonyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-oneas a colorless solid. The material may be recrystallized fromacetonitrile. ¹H NMR (DMSO-d₆) δ 7.79 (t, 1H, J=2 Hz), 7.63–7.49 (m,3H), 7.32 (ab q, 4H, J=21, 9 Hz), 4.10 (t, 2H, J=6 Hz), 3.58 (t, 2H, J=5Hz), 3.36 (s, 3H), 3.19 (t, 2H, J=6 Hz), 2.37 (t, 2H, J=5 Hz), 1.83 (m,4H). LC/MS (ES+): 498.9/500.9 (Cl pattern) (>95% pure by ELSD).

Example 873-(5-Chloro-pyridin-2-yl)-6-methoxy-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-3H-quinazolin-4-one

A mixture of the product from Example 82 (20 mg, 0.04 mmol) in 4N HCl indioxane (5 mL) was stirred at reflux for 3.5 h. The reaction mixture wascooled to rt, and purified with HPLC (15% CH₃CN/H₂O, 20 mL/min) toprovide the desired product as white solid. ESI MS m/z: (M+1)⁺=461.1.

Example 883-(5-Chloro-pyridin-2-yl)-6-methoxy-2-[4-(2-oxo-pyridin-1-yl)-phenyl]-3H-quinazolin-4-one

Following a procedure analogous to that described in Example 87, thetitle compound was obtained as white solid. ESI MS m/z: (M+1)⁺=457.1.

Example 89 Ethyl1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

The title compound was made in Part A of Example 27. High ResolutionMass Spec (M+H)⁺ for C₂₇H₂₅N₄O₅ 485.1827.

Example 901-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid

Ethyl1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(0.5 g, 1.03 mmol) was hydrolyzed with lithium hydroxide (0.13 g, 3mmol) and a mixture of methyl alcohol(5 mL), THF (25 mL) and water (25mL) for 24 h. The reaction was acidified with conc. HCl and theresulting solid filtered off. The product was suspended in 1:1CH₂Cl₂/hexanes, filtered, and dried to afford 0.37 g (79%) white solid;Mass Spec (M+H)⁺ 457.3.

Example 911-(4-methoxyphenyl)-N,N-dimethyl-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

To dimethylamine hydrochloride (0.35 g, 4.3 mmol) in CH₂Cl₂ (20 mL) at0° C. was added 2M trimethylaluminum in hexanes (2.2 mL, 4.3 mmol).After 0.5 h, ethyl1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(0.42 g, 0.86 mmol) was added. The reaction was stirred for 24 h andthen poured into dilute HCl and ice water, extracted with CH₂Cl₂, washedwith brine, and dried (MgSO₄). Purification by chromatography on silicagel and recrystallization from CH₂Cl₂/hexanes afforded 340 mg (81%);High Resolution Mass Spec (M+H)⁺ for C₂₇H₂₆N₅O₄ 484.1980.

Example 92N-({1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl}carbonyl)methanesulfonamide

To1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid (0.2 g, 0.43 mmol) in CH₂Cl₂ (10 mL) was added1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.1 g,0.5 mmol) and TEA (0.18 mL, 1.3 mmol) and the reaction was stirred for15 min. 1-Hydroxybenzotriazole (71 mg, 0.5 mmol) was added and thereaction was stirred for 15 min. Methane sulfonamide (0.125 g, 1.3 mmol)and DMF (1 mL) were added and the reaction was stirred for 72 h. Thesolvents were removed and after purification by HPLC and freeze-drying75 mg (33%) white solid was obtained; High Resolution Mass Spec (M+H)⁺for C₂₆H₂₄N₅O₆S 534.1468.

Example 931-(4-Hydroxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid amide

To ethyl1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(0.2 g, 0.4 mmol) in CH₂Cl₂ (30 mL) at 0° C. was added BBr₃ (0.05 mL,0.5 mmol) and the mixture was stirred for 3 h. The solvents were removedand MeOH (20 mL) and conc. HCl (0.1 mL) were added and heated to refluxfor 24 h to re-esterify. The solvents were removed and the crude esterwas placed in 4 mL of ethylene glycol containing 10% NH₃ and heated in asealed container at 85° C. for 1.5 h. The reaction was cooled and pouredinto water and extracted with EtOAc. Purification by HPLC andfreeze-drying afforded 11 mg (6%) of a white solid; High Resolution MassSpec (M+H)⁺ for C₂₄H₂₄N₅O₄ 446.1840.

Example 941-(4-methoxyphenyl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-(1H-tetraazol-5-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile(0.1 g, 0.23 mmol) in DMF (2 mL) was added NaN₃ (19 mg, 0.29 mmol) andNH₄Cl (21 mg, 0.38 mmol) and the reaction was heated to 105° C. for 24h. The reaction was cooled, water (1 mL) was added, and the resultingsolid filtered off and dried. The solid was placed in DMF (1 mL) andtrityl chloride (60 mg, 0.2 mmol) and pyridine (0.2 mL) were added andstirred for 24 h. The reaction was quenched with water, extracted withEtOAc, and dried (Na₂SO₄). Purification on silica gel was notsuccessful. The trityl group was removed with TFA (0.5 mL) in CH₂Cl₂ for2 h. The solvents were removed and the compound was purified by HPLC andfreeze-dried to afford 10 mg (9%) of a white solid; High Resolution MassSpec (M+H)⁺ for C₂₅H₂₁N₈O₃ 481.1749.

Example 953-{4-[dimethylamino)methyl]-1,3-oxazol-2-yl}-1-(4-methoxyphenyl)-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(0.161 g, 0.35 mmol) was added excess 1,3-dichloroacetone (0.5 g). Thereaction was heated to 130° C. for 24 h. The reaction was cooled andexcess 40% Me₂ in water was added and the mixture stirred for 48 h. Thesolvents were removed and the residue chromatographed with 5%MeOH/CH₂Cl₂ with 1% NH₃ to afford a tan solid (36 mg) that appeared tobe the chloro-intermediate. The solid was placed in ethylene glycol (1mL) and 40% Me₂N/water (1.5 mL) and heated at 80° C. for 3 h. Thereaction was cooled and extracted with EtOAc. Purification by HPLC andfreeze-drying afforded 35 mg (19%) of a white solid; High ResolutionMass Spec (M+H)⁺ for C₃₀H₂₈N₆O₄ 537.2268.

Example 963-{4-[dimethylamino)methyl]-1,3-oxazol-2-yl}-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(0.142 g, 0.31 mmol) was added excess 1,3-dichloroacetone (0.2 g). Thereaction was heated to 130° C. for 24 h. The reaction was cooled andexcess 40% Me₂ in water was added and the resulting mixture stirred for48 h. Repeated purification by HPLC and freeze-drying afforded 2 mg(1.2%) of a white solid; High Resolution Mass Spec (M+H)⁺ for C₃₀H₃₃N₆O₄541.2582.

Example 971-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperazinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part A. Toethyl-6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo(3,4-c)pyridine-3-carboxamide(0.52 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.32 g, 1.4mmol), and K₂CO₃ (0.22 g, 1.6 mmol) was added DMSO (5 mL). The mixturewas degassed with N₂. CuI (38 mg, 0.2 mmol) was added and the reactionwas heated to 130° C. for 18 h. The reaction was diluted with EtOAc andwater, extracted with EtOAc, and dried (MgSO₄). Purification bychromatography on silica gel using 5% MeOH/CH₂Cl₂ afforded 0.2 g (33%)of a foam; Mass Spec (M+H)⁺ 624.6.

Part B. The product of Part A (0.2 g, 0.32 mmol) was hydrogenated at 40psi in the presence of 10% palladium on carbon for 24 h. The reactionwas filtered and then heated with 5% NH₃ in ethylene gylcol in a sealedvial for 1.5 h at 80° C. The reaction was diluted with water andextracted with EtOAc. Purification by HPLC and freeze-drying afforded 30mg (16%) of a white solid; High Resolution Mass Spec (M+H)⁺ forC₂₄H₂₅N₆O₄ 461.1938.

Example 981-(4-methoxyphenyl)-3-(methylsulfonyl)-6-[4-(2-oxo-1-piperazinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To6-(4-iodophenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo(3,4-c)pyridin-7-one(0.55 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.35 g, 1.4mmol), and K₂CO₃ (0.23 g, 1.6 mmol) was added DMSO (5 mL). The mixturewas degassed with N₂. CuI (39 mg, 0.21 mmol) was added and the reactionwas heated to 130° C. for 18 h. The reaction was diluted with EtOAc andwater, extracted with EtOAc, and dried (MgSO₄). Purification of theintermediate by chromatography on silica gel using 5% MeOH/CH₂Cl₂ wasfollowed by deprotection in refluxing TFA. Purification by HPLC andfreeze-drying afforded 175 mg (27%) of a white solid; High ResolutionMass Spec (M+H)⁺ for C₂₄H₂₆N₆O₅S 496.1650.

Example 991-(4-Methoxy-phenyl)-3-(4-methyl-oxazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

Part A. To1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(1 g, 2 mmol) was added excess 1,3-dichloroacetone (2 g). The reactionwas heated to 130° C. for 24 h. The reaction was cooled and purificationby chromatography using 0–3% MeOH in CH₂Cl₂ afforded 0.53 g (42%) whitesolid; ¹H NMR (CDCl₃) δ 7.75 (s, 1H), 7.53 (d,j=8.8 Hz, 2H), 7.37(d,j=8.8 Hz, 2H), 7.27 (d,j=8.8 Hz, 2H), 6.93 (d,j=9.1 Hz, 2H), 4.60 (s,2H), 4.19 (t,j=6.6 Hz, 2H), 3.81 (3H, s), 3.60 (m, 2H), 3.42 (t,j=6.6Hz, 2H), 2.57 (m, 2H), 1.95 (m, 4H) ppm.

Part B. To the product of Part A (73 mg, 0.13 mmol) was added 10%Palladium on carbon (15 mg) and EtOH (35 mL). The mixture washydrogenated at 40 psi for 1.5 h and then filtered through Celite®. Thesolvent was evaporated and the residue purified by HPLC and freeze-driedto afford 40 mg (59%) of a white solid; High Resolution Mass Spec (M+H)⁺for C₂₈H₂₈N₅O₄ 498.2126.

Example 1001-(4-Methoxy-phenyl)-3-(4-methyl-oxazol-2-yl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

Part A. To1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(0.1 g, 0.20 mmol) was added excess 1,3-dichloroacetone (0.5 g). Thereaction was heated to 130° C. for 24 h. The reaction was cooled andpurification by chromatography using 0–3% MeOH in CH₂Cl₂ afforded 0.08 g(69%) of a tan solid.

Part B. To the product of Part A (80 mg, 0.15 mmol) was added 10%Palladium on carbon (20 mg) and EtOH (35 mL). The mixture washydrogenated at 40 psi for 0.3 h and then filtered through Celite®. Thesolvent was evaporated and the residue purified by HPLC and freeze-driedto afford 10 mg (13%) of a white solid; High Resolution Mass Spec (M+H)⁺for C₂₈H₂₄N₅O₃ 494.1829.

Example 1013-Acetyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To3-bromo-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one(0.11 g, 0.22 mmol) was added THF (25 mL), 1-(ethoxyvinyl)tributyltin(0.078 mL, 0.23 mmol), and LiCl (27 mg, 0.65 mmol) and the mixture wasdegassed with N₂ for 15 min. Tetrakistriphenylphosphine Palladium(0) (12mg, 0.01 mmol) was added and the reaction was heated to reflux 24 h. Thereaction was cooled to rt and treated with 1N HCl for 24 h. Afterextraction with EtOAc and drying (MgSO₄), the product was purified bysilica gel (mixed with KF) chromatography using 0–3% MeOH in CH₂Cl₂ andby HPLC to afford 6 mg (6%); High Resolution Mass Spec (M+H)⁺ forC₂₆H₂₃N₄O₄ 455.1713.

Example 1023-(4,5-Dihydro-1H-imidazol-2-yl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To ethylene diamine (0.4 mL, 6 mmol) in toluene (25 mL) at 0° C. wasadded 2M trimethylaluminum in heptane (1 mL, 2 mmol) and, after stirringfor 20 min,1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.1 g, 0.2 mmol) was added and the reaction was heatedto 60° C. for 24 h. The reaction was quenched with water and MeOH, dried(Na₂SO₄), filtered, and concentrated. The residue was suspended in EtOAcand filtered. Purification by HPLC and freeze-drying afforded 15 mg(12%) of a white solid; High Resolution Mass Spec (M+H)⁺ for C₂₇H₂₅N₆O₃481.2003.

Example 1031-(4-Methoxy-phenyl)-3-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To N-methylethylene diamine (0.47 mL, 5 mmol) in toluene (25 mL) at 0°C. was added 2M trimethylaluminum in heptane (2.7 mL, 5 mmol) and, afterstirring for 20 min,1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.88 g, 1.8 mmol) was added and the reaction washeated to 100° C. for 24 h. The reaction was quenched with water andMeOH, dried (Na₂SO₄), filtered, and concentrated. The residue wassuspended in EtOAc and filtered. Purification by HPLC and freeze-dryingafforded 120 mg (11%) of a white solid; Mass Spec (M+H)⁺ 499.3.

Example 104

1-(4-Methoxy-phenyl)-3-(1-methyl-1H-imidazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To Example 103 (0.085 g, 0.14 mmol) in dioxane (15 mL) was added KMNO₄(48 mg, 0.3 mmol) and the reaction was heated to 100° C. After 2 hexcess KMnO₄ was added to accelerate the reaction and it was heated 24h. Filtration and purification by HPLC and freeze-drying afforded 10 mg(11.7%) of a white solid; Mass Spec (M+H)⁺ 497.3.

Example 1051-(4-Methoxy-phenyl)-3-methyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.59 g, 1.2 mmol) in THF (25 mL) was added 2M LiBH₄ inTHF(0.96 mL, 1.9 mmol) and the reaction was heated to reflux for 2.5 h.To the crude alcohol were added CH₂Cl₂ (25 mL) and PBr₃ (0.14 mL) andthe reaction was stirred 24 h. Extraction with CHCl₃, washing withwater, and drying (Na₂SO₄) afforded a crude bromo-compound. Thebromo-compound was heated in AcOH (15 mL) and activated Zn (0.39 g, 6mmol) at 120° C. for 24 h. Purification by HPLC and freeze-dryingafforded 30 mg (58%) of a white solid; High Resolution Mass Spec (M+H)⁺for C₂₅H₂₇N₄O₃ 431.2092.

Example 1063-Hydroxymethyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.2 g, 0.4 mmol) in THF (25 mL) was added 2M LiBH₄ inTHF (0.31 mL, 0.66 mmol) and the reaction was heated to reflux for 3 h.After extraction into EtOAc and washing with water and brine, theproduct crystallized out upon standing; High Resolution Mass Spec (M+H)⁺for C₂₅H₂₃N₄O₄ 443.1730.

Example 1073-(1-Hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one

To1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.1, 0.2 mmol) in THF (15 mL) at 0° C. was addedMeMgBr (0.21 mL, 0.6 mmol) and the reaction was stirred at rt for 24 h.The reaction was quenched with water and purified by HPLC to afford 47mg (48%) of a white solid; Mass Spec (M+H)⁺ 475.

Example 1083-(1-Hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared following the procedure employed forExample 107 using the product of Part A of Example 27. ESI MS m/z 471(M+H).

Example 1092-Dimethylamino-N-{1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}-N-methylacetamidehydrochloric acid salt

Part A. A mixture of6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (5 g, 9.7 mmol), K₂CO₃ (1.5 g, 110 mmol),piperidine-2-one (1.2 g, 11.6 mmol), CuI (228 mg, 1.2 mmol), and DMSO(10 mL) was heated at 140° C. for 24 h. The solution was cooled to rt,diluted with EtOAc, washed with brine, dried over Na₂SO₄, filtered, andevaporated. Purification of the residue by column chromatographyprovided the corresponding aryl lactam (1.3 g, 28%): ESI MS m/z 489(M+H)⁺.

Part B. To a solution of the ester from above (500 mg, 1.02 mmol) in THF(5 mL), MeOH (3 mL), and H₂O (2 mL) was added LiOH (52 mg, 1.2 mmol) atrt. The reaction mixture was stirred for 1 h, acidified withDowex-50W-hydrogen ion-exchange resin, filtered, and evaporated toprovide the corresponding acid as a white solid (471 mg, 99%) which wasused without further purification: ESI MS m/z 461 (M+H)⁺.

Part C. To a cold (0° C.) solution of the acid (500 mg, 1.09 mmol) fromabove in THF (10 mL) was added Et₃N (0.17 mL, 1.2 mmol) followed byisobutyl chloroformate (0.16 mL, 1.2 mmol). The reaction mixture wasstirred for 1 h then NaBH₄ (82 mg, 2.2 mmol) was added. After 30 min, asmall piece of ice was added and the reaction mixture was stirred for anadditional 2 h. The mixture was diluted with EtOAc, washed with 0.1 NHCl and brine, dried (Na₂SO₄), filtered and concentrated. Purificationof the residue on silica gel provided the corresponding alcohol as awhite solid (317 mg, 71%): ESI MS m/z 447 (M+H)⁺.

Part D. A solution of the alcohol (317 mg, 0.71 mmol) prepared above inCH₂Cl₂ (7 mL) was cooled to 0° C. then 1M PBr₃ in CH₂Cl₂ (0.78 mL, 0.78mmol) was added. The cooling bath was removed; the reaction mixture wasstirred for 3 h, and then diluted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated toprovide the corresponding bromomethyl compound (369 mg, >99%) which wasused without further purification: ESI MS m/z 509, 511 (M+H)⁺.

Part E. A solution of the bromomethyl compound (489 mg, 0.96 mmol)prepared above and NaN₃ (67 mg, 1.1 mmol) in DMF (10 mL) was heated at60° C. overnight. The reaction mixture was cooled to rt, diluted withEtOAc, washed with 1% aqueous LiCl, dried over Na₂SO₄, filtered, andconcentrated to provide the corresponding azide (450 mg, 99%) as a whitefoam: ESI MS m/z 472 (M+H)⁺.

Part F. The azide (213 mg, 0.45 mmol) made above was dissolved in MeOH(5 mL) then 10% Pd/C (30 mg, 10 mol %) was added and the reactionmixture was exposed to an atmosphere of H₂ (balloon). After 3 h, thereaction mixture was filtered through Celite® and concentrated.Purification of the residue on silica gel provided the correspondingaminomethyl compound (151 mg, 75%): ESI MS m/z 446 (M+H)⁺.

Part G. The aminomethyl prepared above (367 mg, 0.82 mmol) was added toa solution containing N,N-dimethylglycine (127 mg, 1.2 mmol), Hünig'sbase (0.36 mL, 2.1 mmol), EDCI (237 mg, 1.2 mmol), HOAt (catalytic), andCH₂Cl₂ (1.6 mL). The reaction mixture was stirred at rt overnight thendiluted with EtOAc. The organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated. Chromatography of the residue onsilica gel followed by treatment with 2 N HCl and lyophilizationprovided the title compound: ESI MS m/z 531 (M+H)⁺.

Example 1102-Dimethylamino-N-{1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}acetamidehydrochloric acid salt

The title compound was prepared according to the procedures describedfor Example 109: ESI MS m/z 527 (M+H)⁺.

Example 111N-{1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}-2-pyridin-2-yl-acetamidehydrochloric acid salt

The title compound was prepared according to the procedures describedfor Example 109: ESI MS m/z 565 (M+H)⁺.

Example 112N-{1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ylmethyl}-2-(1-oxypyridin-2-yl)acetamide

The title compound was prepared according to the procedures describedfor Example 109: APCI MS m/z 581 (M+H)⁺.

Example 1135-Chloro-N-(5-chloropyridin-2-yl)-3-methoxy-2-[4-(2-oxopiperidin-1-yl)-benzoylamino]benzamide

Part A. To a mixture of methyl 4-iodobenzoate (10.0 g, 0.038 mol),δ-valerolactam (4.53 g, 0.046 mol), PNT (0.76 g, 4.20 mmol), and K₂CO₃(5.80 g, 0.042 mol) in DMSO (20 mL) was added CuI (0.87 g, 4.58 mmol)and the reaction mixture was heated at 110° C. for 24 h. The solutionwas cooled to rt, diluted with CH₂Cl₂, washed with brine, dried overMgSO₄, filtered, and evaporated. Purification of the residue by columnchromatography (eluting with 98:2 CH₂Cl₂/MeOH) provided thecorresponding lactam (3.4 g, 38%): ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d,2H), 7.35 (d, 2H), 3.91 (s, 3H), 3.70 (m, 2H), 2.58 (m, 2H), 1.96 (m,4H); APCI MS m/z 234 (M+H)⁺.

Part B. To a solution of the ester made above (1.0 g, 4.29 mmol) in THF(16 mL) and H₂O (4 mL) at 0° C. was added LiOH (198 mg, 4.72 mmol). Thereaction mixture was stirred at rt for 14 h and partitioned betweenEtOAc and 2M HCl solution. The organics were washed with brine, driedover MgSO₄, filtered, and evaporated to provide the corresponding acidas a white solid (525 mg, 56%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.95 (s,1H), 8.07 (d, 2H), 7.57 (d, 2H), 3.81 (m, 2H), 2.57 (m, 2H), 2.00 (m,4H); ESI MS m/z 220 (M+H)⁺.

Part C. To a suspension of the acid (0.21 g, 0.96 mmol) made above inCH₂Cl₂ (5 mL) was added SOCl₂ (0.21 mL, 2.89 mmol) and the reactionmixture was stirred at rt for 3 h. The reaction mixture was concentratedto give the crude acid chloride as a white solid. The crude acidchloride was used directly in the next step.

Part D. To a solution of2-amino-5-chloro-N-(5-chloropyridin-2-yl)-3-methoxy-benzamide (150 mg,0.48 mmol), DMAP (24 mg, 0.19 mmol), and pyridine (95 mg, 1.21 mmol) inCH₂Cl₂ (5 mL) was added a solution of the crude acid chloride made abovein CH₂Cl₂ (5 mL) and the reaction mixture was stirred at rt for 20 h.The reaction mixture was diluted with CH₂Cl₂; washed with water, 0.25 MNaOH solution, and brine; dried over MgSO₄; filtered; and concentrated.Purification of the residue by column chromatography provided the titlecompound as a white solid (99 mg, 40%): ¹H NMR (300 MHz, DMSO-d₆) δ10.78 (s, 1H) 9.73 (s, 1H), 8.36 (d, 1H), 7.99 (d, 1H), 7.87 (m, 3H),7.33 (m, 3H), 7.27 (d, 1H), 3.85 (s, 3H) 3.64 (m, 2H), 2.41 (m, 2H),1.86 (m, 4H); ESI MS m/z 513 (M+H)⁺.

Example 1145-Chloro-N-(5-chloropyridin-2-yl)-3-methoxy-2-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]benzamide

The title compound was prepared according to the procedures describedfor Example 113: ¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (s, 1H), 9.89 (s,1H), 8.37 (d, 1H), 8.09 (d, 1H), 8.00 (d, 2H), 7.88 (dd, 1H), 7.67 (dd,1H), 7.52 (m, 3H), 7.39 (d, 1H), 7.29 (d, 1H), 6.50 (d, 1H), 6.35 (dt,1H), 3.89 (s, 3H); ESI MS m/z 509 (M+H)⁺.

Example 1156-[4-(1,1-Dioxo-116-isothiazolidin-2-yl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid amide

Part A. To6-(4-amino-phenyl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.35 g, 0.86 mmol) and 3-chloropropanesulfonylchloride (0.125 mL, 1 mmol) in THF (20 mL) was added triethylamine(0.144 mL, 1 mmol) and the reaction was stirred 24 h. Potassiumtert-butoxide (0.31 g, 2.5 mmol) was added and the reaction was stirred24h. The ester was purified by chromatography using 1–5% MeOH in CH₂Cl₂.

Part B. The ester from Part A was placed in a sealed tube containing 10%NH₃ in ethylene glycol and heated to 80° C. for 3 h. The reaction wascooled, quenched with water, and extracted with EtOAc. Purification byHPLC and freeze-drying afforded 19 mg (4.6%) of a white solid; HighResolution Mass Spec (M+H)⁺ for C₂₃H₂₄N₅O₅S 482.1493.

Example 116N-Hydroxy-3-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamidine

Part A. To a solution of3-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-benzonitrile(0.403 g, 0.793 mmol) was added 2-hydroxypyridine (0.226 g, 2.38 mmol),potassium carbonate (0.328 g, 2.38 mmol) and 3 mg CuI. The reactionmixture was refluxed for 18 h, cooled and quenched with HCl (1N). Theorganics were extracted with ethylacetate (2×10 mL), dried (MgSO₄), andconcentrated to afford the desired crude product. ESI mass spectrum 476(M+H).

Part B. The crude product from part A (0.18 g, 0.37 mmol) in anhydrousmethyl alcohol (10 mL) was treated with hydroxylamine hydrochloride(0.04 g, 0.57 mmol) and excess triethylamine (0.5 mL). The reactionmixture was stirred at rt for 48 h, concentrated, and purified viareverse phase HPLC to provide 78 mg (40%) of the title compound. ESImass spectrum 509 (M+H).

Example 117N-Methoxy-3-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamidine

The product from part A in Example 116 (0.2 g) was dissolved in methylalcohol (10 mL). HCl gas was bubbled for 5 min and capped. The reactionmixture was stirred at rt for 24 h, concentrated, and evaporated to asemi solid mass. The crude was redissolved in methyl alcohol (10 mL) andthis mixture was added 0.5 g of O-methoxyhydroxylamine hydrochloride and1 mL of triethylamine. The reaction mixture was stirred at rt for 24 hand concentrated and purified via HPLC. Colorless crystals of the titlecompound were obtained. ESI mass spectrum 523 (M+H).

Example 1181-(3-cyano-4-fluorophenyl-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

The condensation of 3-chloro-4-fluoro-phenylhydrazine with1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one afforded1-(3-chloro-4-fluoro-phenyl)-6-(4-iodo-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.This was then treated under Ullman conditions with 2-hydroxypyridine toafford1-(3-chloro-4-fluoro-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.ESI mass spectrum 482 (M+H). The conversion of chlorine to a cyano groupwas accomplished via palladium catalyzed cyanation methodology employingzinc cyanide. MS (AP⁺): 473.2 (M+H).

Example 1191-(3-Aminomethyl-4-fluoro-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid amide

The cyano group of Example 118 was reduced to benzylamine throughhydrogenation (Parr shaker, MeOH, Pd/C 10%, AcOH) and purified via HPLC.ESI mass spectrum 477 (M+H).

Example 1202-{7-Oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzenesulfonamide

The title compound was synthesized in a similar fashion as Example 6,except that 2-sulfonamidophenyl-hydrazine was used in place of4-methoxyhydrazine hydrochloride. MS (AP⁺): 534.1 (M+H).

Example 1212-{7-Oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzenesulfonamide

The title compound was synthesized in a similar fashion as Example 6,except that 2-sulfonamidophenyl-hydrazine was used in place of4-methoxyhydrazine hydrochloride. MS (AP⁺): 530.1 (M+H).

Example 122N-Acetyl-2-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzenesulfonamide

The sulfonamide of Example 121 was acetylated with acetic anhydride toafford the title compound. MS (ES⁺): 572.1 (M+H).

Example 1231-(3-Chloro-phenyl)-3-methanesulfonyl-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

The title compound was synthesized in the same fashion as described forExample 86, parts A and B, by substituting 2-pyridone forδ-valerolactam. ¹H NMR (CDCl₃) δ 7.61 (t, 1H, J=2 Hz), 7.51–7.28 (m,9H), 6.66 (d, 1H, J=9 Hz), 6.26 (td, 1H, J=7, 1 Hz), 4.21 (t, 2H, J=7Hz), 3.38 (t, 2H, J=7 Hz), 3.33 (s, 3H). LC/MS (ES+): 494.9/496.9.9 (Clpattern) (>95% by ELSD).

Example 1241-(4-Methoxy-phenyl)-3-methyl-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

To3-hydroxymethyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one(65 mg, 0.15 mmol) in CH₂Cl₂ (10 mL) was added triethylsilane (0.1 mL)and TFA (0.05 mL). After 2 h more triethylsilane (0.2 mL) and TFA (0.1mL) were added and the reaction was stirred for 72 h. The reaction wasnot proceeding so the solvents were stripped and replaced with aceticacid (10 mL), triethylsilane (0.5 mL), and TFA (0.1 mL). The reactionwas heated 24 h at 80° C. Mass spectra indicated only the acetyl productformed. The solvents were removed. The acetyl group was removed bystirring with LiOH (0.1 g) in THF/H₂O for 3 h. The reaction was quenchedwith 1N HCl, extracted with EtOAc, and dried (MgSO₄) to recover thealcohol. To the alcohol in CHCl₃ was added PBr₃ and the reaction wasstirred 24 h. The reaction was quenched with ice water, extracted withCHCl₃, and dried (Na₂SO₄). To the crude bromide were added activated Zn(80 mg) and acetic acid (10 mL) and heated to 120° C. for 24 h. Theproduct was purified by silica gel chromatography using 0–3% MeOH inCH₂Cl₂ and recrystallized from CH₃CN/H₂O to afford 22 mg (35%); MassSpec (M+H)⁺ 427.3.

Example 1253-(4-Methoxy-phenyl)-5-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-4-one

Part A. Para-anisidine (7 g) was dissolved in TFA (10 mL) and thesolution cooled to 0° C. To this ice cold solution was added dropwise anaqueous solution containing sodium nitrite (4.8 g). After 30 min wasadded an aqueous solution containing sodium azide (4.43 g). The reactionbecame exothermic and was stirred for an additional 2 h, quenched withwater (1 L), and the organics extracted with methylene chloride (2×100mL) and dried (magnesium sulfate). Concentration afforded the desiredazide that was immediately redissolved in toluene (100 mL). To thissolution was added1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (21.85g) and the solution was gently refluxed for 48 h. Toluene wasconcentrated and the crude was poured directly onto a silica gel columnand eluted with hexane:ethyl acetate 7:3 to afford approx 1.2 g5-(4-iodo-phenyl)-3-(4-methoxy-phenyl)-3,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-4-one.ESI mass spectrum m/z 447 (M+H).

Part B. The compound obtained from part A (0.41 g) was treated with2-hydroxypyridine under the Ullman conditions as previously described toobtain the title compound (50 mg). ESI mass spectrum m/z 414 (M+H).

Example 1263-(4-Methoxy-phenyl)-5-[4-(2-oxo-piperidin-1-yl)-phenyl]-3,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-4-one

The Ullman coupling methodology using the δ-valerolactam previouslydescribed to afforded the title compound after purification via silicachromatography. ESI mass spectrum m/z 418 (M+H).

Example 1273-(3-Chloro-phenyl)-5-[4-(2-oxo-piperidin-1-yl)-phenyl]-3,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-4-one

In an identical procedure described for the para-methoxy-triazoloanalogs the m-chlorophenyl title compound was prepared. ESI massspectrum m/z 422 (M+H).

Example 1283-(3-Chloro-phenyl)-5-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-4-one

In an identical procedure described for the para-methoxy-triazoloanalogs the m-chlorophenyl title compound was prepared. ESI massspectrum m/z 418 (M+H).

Example 1291-(3-Chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one

1-(3-Chloro-phenyl)-7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (0.098 g, 0.216 mmol) was dissolved into THF (10 mL).Methylmagnesium bromide (0.179 mL, 0.539 mmol) was added dropwise to thereaction. The reaction was stirred at rt overnight. The reaction wasquenched with 1N HCl (100 mL) and extracted into ethyl acetate (4×50mL), washed with brine (1×50 mL), and dried (MgSO₄). Purification bysilica gel chromatography using 0%–100% ethyl acetate/hexane gradientfollowed by a 0%–100% methanol/ethyl acetate gradient as the eluentsafforded 54.6 mg (53%) of the title product: ¹H NMR (CDCl₃) δ 7.59 (s,1H), 7.48–7.37 (m, 7H), 7.33–7.28 (m, 2H), 6.66 (d,j=9.2 Hz, 1H), 6.25(dt,j=1.1 Hz, 6.6 Hz, 1H), 4.16 (t,j=6.6 Hz, 2H), 3.19 (t,j=6.6 Hz, 2H),1.68 (s, 6H) ppm; ESI Mass Spec 475.3(M+H)⁺.

Example 1301-(3-Chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one

The meta-chloro-lactam-ethyl ester (0.036 g, 0.078 mmol) was dissolvedinto THF (6 mL). Methylmagnesium bromide (0.07 mL, 0.196 mmol) was addeddropwise to the reaction. The reaction was stirred at rt overnight. Thereaction was quenched with 1N HCl (50 mL) and extracted into ethylacetate (4×25 mL), washed with brine (1×25 mL), and dried (MgSO₄).Purification by silica gel chromatography using 0%–100% ethylacetate/hexane gradient followed by a 0%–100% methanol/ethyl acetategradient as the eluents afforded 15.7 mg (42%): ¹H NMR (CDCl₃) δ 7.59(s, 1H), 7.47–7.43 (m, 1H), 7.36–7.24 (m, 6H), 4.12 (t,j=6.6 Hz, 2H),3.65–3.55 (m, 2H), 3.16 (t,j=6.6 Hz, 2H), 2.60–2.49 (m, 2H), 1.96–1.93(m, 4H), 1.67 (s, 6H) ppm; Mass Spec (M+H)⁺ 479.3.

Example 1313-(7-Oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamide

The product from Example 116, part A (0.05 g) was dissolved indichloromethane (10 mL). To this was added sodium hydroxide (1N, 5 mL),hydrogen peroxide (3 mL), and tetrabutylammonium-hydroxide (0.01 g). Thereaction mixture was stirred at rt for 24 h and concentrated. Quenchedwith water (50 mL) and the organics extracted with ethylacetate (2×50mL), dried (MgSO₄) and concentrated. The crude was purified via prepHPLC to a colorless solid. ESI mass spectrum 494(M+H) and 492(M−H).

Example 1323-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide

Step A. 4-(2-Oxo-2H-pyridin-1-yl)benzoyl chloride (0.44 g, 2.05 mmol)was stirred in CH₂Cl₂ (10 mL) at RT under N₂. Cis-1,2-diaminocyclohexane(0.5 mL, 4.17 mmol) was quickly added as one portion to the stirringsolution. The mixture was stirred at rt for 10 min. It was quenched withdiluted aqueous HCl, and then extracted with EtOAc (2×). The water layerwas basified with 1N NaOH, and then extracted with EtOAc (2×). Theorganic layer was washed with H₂O, brine, dried over MgSO₄, andconcentrated to dryness. FCC (silica gel, CH₂Cl₂, then EtOAc) gave pureN-cis-1,2-(2-amino-cyclohexyl)-4-(2-oxo-2H-pyridin-1-yl)benzamide (0.54g, yield: 84%).

Step B. To a solution of the product from step A (50 mg, 0.16 mmol) inDMF (0.5 mL) was added 3-chloro-1H-indole-6-carboxylic acid (47 mg, 0.24mmol) followed by the addition of HATU (80 mg, 0.21 mmol) and DIEA (0.08mL, 0.46 mmol). The mixture was stirred at rt overnight. The residue wasdiluted with MeOH and purified by LC/MS to give the desired3-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide(14 mg, yield: 18%). LC/MS-ESI, 489.4 (M+H).

Example 1335-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI(M+H)⁺ 489.6.

Example 1345-chloro-N-(1,2-cis-2-{[4-(2-oxopyridin-1(2H)-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 456.6.

Example 1355-chloro-N-(1,2-cis-2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 457.4.

Example 1365-chloro-N-(1,2-cis-2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 490.4.

Example 1373-chloro-N-(1,2-cis-2-{[4-(2-oxopyrazin-1(2H)-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 490.4.

Example 1385-chloro-N-(1,2-cis-2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)thiophene-2-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 457.4.

Example 1395-chloro-N-(1,2-cis-2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-2-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 493.4.

Example 1403-chloro-N-(1,2-cis-2-{[4-(2-oxopiperidin-1-yl)benzoyl]amino}cyclohexyl)-1H-indole-6-carboxamide

Following a procedure analogous to that described in Example 132, thetitle compounds was obtained. LC/MS ESI (M+H)⁺ 493.4.

The following tables contain representative examples of the presentinvention. Each entry in each table is paired with each formula at thestart of the table. For example, in Table 1, example 1-1 is paired witheach of the formulae shown. The following nomenclature is intended forgroup A in the following tables.

TABLE 1

Ex# A G 1-1. phenyl 4-methoxyphenyl 1-2. 2-pyridyl 4-methoxyphenyl 1-3.3-pyridyl 4-methoxyphenyl 1-4. 2-pyrimidyl 4-methoxyphenyl 1-5.2-Cl-phenyl 4-methoxyphenyl 1-6. 2-F-phenyl 4-methoxyphenyl 1-7. phenyl2-aminomethylphenyl 1-8. 2-pyridyl 2-aminomethylphenyl 1-9. 3-pyridyl2-aminomethylphenyl 1-10. 2-pyrimidyl 2-aminomethylphenyl 1-11.2-Cl-phenyl 2-aminomethylphenyl 1-12. 2-F-phenyl 2-aminomethylphenyl1-13. phenyl 3-aminomethylphenyl 1-14. 2-pyridyl 3-aminomethylphenyl1-15. 3-pyridyl 3-aminomethylphenyl 1-16. 2-pyrimidyl3-aminomethylphenyl 1-17. 2-Cl-phenyl 3-aminomethylphenyl 1-18.2-F-phenyl 3-aminomethylphenyl 1-19. phenyl 2-amidophenyl 1-20.2-pyridyl 2-amidophenyl 1-21. 3-pyridyl 2-amidophenyl 1-22. 2-pyrimidyl2-amidophenyl 1-23. 2-Cl-phenyl 2-amidophenyl 1-24. 2-F-phenyl2-amidophenyl 1-25. phenyl 2-amido-4-methoxy-phenyl 1-26. 2-pyridyl2-amido-4-methoxy-phenyl 1-27. 3-pyridyl 2-amido-4-methoxy-phenyl 1-28.2-pyrimidyl 2-amido-4-methoxy-phenyl 1-29. 2-Cl-phenyl2-amido-4-methoxy-phenyl 1-30. 2-F-phenyl 2-amido-4-methoxy-phenyl 1-31.phenyl 3-amidophenyl 1-32. 2-pyridyl 3-amidophenyl 1-33. 3-pyridyl3-amidophenyl 1-34. 2-pyrimidyl 3-amidophenyl 1-35. 2-Cl-phenyl3-amidophenyl 1-36. 2-F-phenyl 3-amidophenyl 1-37. phenyl 3-chlorophenyl1-38. 2-pyridyl 3-chlorophenyl 1-39. 3-pyridyl 3-chlorophenyl 1-40.2-pyrimidyl 3-chlorophenyl 1-41. 2-Cl-phenyl 3-chlorophenyl 1-42.2-F-phenyl 3-chlorophenyl 1-43. phenyl 3-amino-4-chloro-phenyl 1-44.2-pyridyl 3-amino-4-chloro-phenyl 1-45. 3-pyridyl3-amino-4-chloro-phenyl 1-46. 2-pyrimidyl 3-amino-4-chloro-phenyl 1-47.2-Cl-phenyl 3-amino-4-chloro-phenyl 1-48. 2-F-phenyl3-amino-4-chloro-phenyl 1-49. phenyl 2-aminosulfonyl-phenyl 1-50.2-pyridyl 2-aminosulfonyl-phenyl 1-51. 3-pyridyl 2-aminosulfonyl-phenyl1-52. 2-pyrimidyl 2-aminosulfonyl-phenyl 1-53. 2-Cl-phenyl2-aminosulfonyl-phenyl 1-54. 2-F-phenyl 2-aminosulfonyl-phenyl 1-55.phenyl 2-aminosulfonyl-4- methoxyphenyl 1-56. 2-pyridyl2-aminosulfonyl-4- methoxyphenyl 1-57. 3-pyridyl 2-aminosulfonyl-4-methoxyphenyl 1-58. 2-pyrimidyl 2-aminosulfonyl-4- methoxyphenyl 1-59.2-Cl-phenyl 2-aminosulfonyl-4- methoxyphenyl 1-60. 2-F-phenyl2-aminosulfonyl-4- methoxyphenyl 1-61. phenyl3-(1′,2′,4′-triazolin-5′-on- 3′-yl)phenyl 1-62. 2-pyridyl3-(1′,2′,4′-triazolin-5′-on- 3′-yl)phenyl 1-63. 3-pyridyl3-(1′,2′,4′-triazolin-5′-on- 3′-yl)phenyl 1-64. 2-pyrimidyl3-(1′,2′,4′-triazolin-5′-on- 3′-yl)phenyl 1-65. 2-Cl-phenyl3-(1′,2′,4′-triazolin-5′-on- 3′-yl)phenyl 1-66. 2-F-phenyl3-(1′,2′,4′-triazolin-5′-on- 3′-yl)phenyl 1-67. phenyl1-aminoisoquinolin-6-yl 1-68. 2-pyridyl 1-aminoisoquinolin-6-yl 1-69.3-pyridyl 1-aminoisoquinolin-6-yl 1-70. 2-pyrimidyl1-aminoisoquinolin-6-yl 1-71. 2-Cl-phenyl 1-aminoisoquinolin-6-yl 1-72.2-F-phenyl 1-aminoisoquinolin-6-yl 1-73. phenyl 1-aminoisoquinolin-7-yl1-74. 2-pyridyl 1-aminoisoquinolin-7-yl 1-75. 3-pyridyl1-aminoisoquinolin-7-yl 1-76. 2-pyrimidyl 1-aminoisoquinolin-7-yl 1-77.2-Cl-phenyl 1-aminoisoquinolin-7-yl 1-78. 2-F-phenyl1-aminoisoquinolin-7-yl 1-79. phenyl 4-aminoquinazol-6-yl 1-80.2-pyridyl 4-aminoquinazol-6-yl 1-81. 3-pyridyl 4-aminoquinazol-6-yl1-82. 2-pyrimidyl 4-aminoquinazol-6-yl 1-83. 2-Cl-phenyl4-aminoquinazol-6-yl 1-84. 2-F-phenyl 4-aminoquinazol-6-yl 1-85. phenyl4-aminoquinazol-7-yl 1-86. 2-pyridyl 4-aminoquinazol-7-yl 1-87.3-pyridyl 4-aminoquinazol-7-yl 1-88. 2-pyrimidyl 4-aminoquinazol-7-yl1-89. 2-Cl-phenyl 4-aminoquinazol-7-yl 1-90. 2-F-phenyl4-aminoquinazol-7-yl 1-91. phenyl 3-aminobenzisoxazol-5-yl 1-92.2-pyridyl 3-aminobenzisoxazol-5-yl 1-93. 3-pyridyl3-aminobenzisoxazol-5-yl 1-94. 2-pyrimidyl 3-aminobenzisoxazol-5-yl1-95. 2-Cl-phenyl 3-aminobenzisoxazol-5-yl 1-96. 2-F-phenyl3-aminobenzisoxazol-5-yl 1-97. phenyl 3-aminobenzisoxazol-6-yl 1-98.2-pyridyl 3-aminobenzisoxazol-6-yl 1-99. 3-pyridyl3-aminobenzisoxazol-6-yl 1-100. 2-pyrimidyl 3-aminobenzisoxazol-6-yl1-101. 2-Cl-phenyl 3-aminobenzisoxazol-6-yl 1-102. 2-F-phenyl3-aminobenzisoxazol-6-yl 1-103. phenyl 3-aminoindazol-5-yl 1-104.2-pyridyl 3-aminoindazol-5-yl 1-105. 3-pyridyl 3-aminoindazol-5-yl1-106. 2-pyrimidyl 3-aminoindazol-5-yl 1-107. 2-Cl-phenyl3-aminoindazol-5-yl 1-108. 2-F-phenyl 3-aminoindazol-5-yl 1-109. phenyl3-aminoindazol-6-yl 1-110. 2-pyridyl 3-aminoindazol-6-yl 1-111.3-pyridyl 3-aminoindazol-6-yl 1-112. 2-pyrimidyl 3-aminoindazol-6-yl1-113. 2-Cl-phenyl 3-aminoindazol-6-yl 1-114. 2-F-phenyl3-aminoindazol-6-yl 1-115. phenyl indolin-5-yl 1-116. 2-pyridylindolin-5-yl 1-117. 3-pyridyl indolin-5-yl 1-118. 2-pyrimidylindolin-5-yl 1-119. 2-Cl-phenyl indolin-5-yl 1-120. 2-F-phenylindolin-5-yl 1-121. phenyl indolin-6-yl 1-122. 2-pyridyl indolin-6-yl1-123. 3-pyridyl indolin-6-yl 1-124. 2-pyrimidyl indolin-6-yl 1-125.2-Cl-phenyl indolin-6-yl 1-126. 2-F-phenyl indolin-6-yl 1-127. phenyl2-naphthyl 1-128. 2-pyridyl 2-naphthyl 1-129. 3-pyridyl 2-naphthyl1-130. 2-pyrimidyl 2-naphthyl 1-131. 2-Cl-phenyl 2-naphthyl 1-132.2-F-phenyl 2-naphthyl 1-133. phenyl 3-amido-naphth-2-yl 1-134. 2-pyridyl3-amido-naphth-2-yl 1-135. 3-pyridyl 3-amido-naphth-2-yl 1-136.2-pyrimidyl 3-amido-naphth-2-yl 1-137. 2-Cl-phenyl 3-amido-naphth-2-yl1-138. 2-F-phenyl 3-amido-naphth-2-yl 1-139. phenyl3-methylsulfonyl-naphth-2-yl 1-140. 2-pyridyl3-methylsulfonyl-naphth-2-yl 1-141. 3-pyridyl3-methylsulfonyl-naphth-2-yl 1-142. 2-pyrimidyl3-methylsulfonyl-naphth-2-yl 1-143. 2-Cl-phenyl3-methylsulfonyl-naphth-2-yl 1-144. 2-F-phenyl3-methylsulfonyl-naphth-2-yl 1-145. phenyl 3-aminomethyl-naphth-2-yl1-146. 2-pyridyl 3-aminomethyl-naphth-2-yl 1-147. 3-pyridyl3-aminomethyl-naphth-2-yl 1-148. 2-pyrimidyl 3-aminomethyl-naphth-2-yl1-149. 2-Cl-phenyl 3-aminomethyl-naphth-2-yl 1-150. 2-F-phenyl3-aminomethyl-naphth-2-yl 1-151. phenyl 3-fluoro-naphth-2-yl 1-152.2-pyridyl 3-fluoro-naphth-2-yl 1-153. 3-pyridyl 3-fluoro-naphth-2-yl1-154. 2-pyrimidyl 3-fluoro-naphth-2-yl 1-155. 2-Cl-phenyl3-fluoro-naphth-2-yl 1-156. 2-F-phenyl 3-fluoro-naphth-2-yl 1-157.phenyl 3-cyano-naphth-2-yl 1-158. 2-pyridyl 3-cyano-naphth-2-yl 1-159.3-pyridyl 3-cyano-naphth-2-yl 1-160. 2-pyrimidyl 3-cyano-naphth-2-yl1-161. 2-Cl-phenyl 3-cyano-naphth-2-yl 1-162. 2-F-phenyl3-cyano-naphth-2-yl 1-163. phenyl 3-aminosulfonyl-naphth-2-yl 1-164.2-pyridyl 3-aminosulfonyl-naphth-2-yl 1-165. 3-pyridyl3-aminosulfonyl-naphth-2-yl 1-166. 2-pyrimidyl3-aminosulfonyl-naphth-2-yl 1-167. 2-Cl-phenyl3-aminosulfonyl-naphth-2-yl 1-168. 2-F-phenyl3-aminosulfonyl-naphth-2-yl 1-169. phenyl 6-chloro-naphth-2-yl 1-170.2-pyridyl 6-chloro-naphth-2-yl 1-171. 3-pyridyl 6-chloro-naphth-2-yl1-172. 2-pyrimidyl 6-chloro-naphth-2-yl 1-173. 2-Cl-phenyl6-chloro-naphth-2-yl 1-174. 2-F-phenyl 6-chloro-naphth-2-yl

TABLE 2

R^(1a) is CH₃; Ex# A G 2-1. phenyl 4-methoxyphenyl 2-2. 2-pyridyl4-methoxyphenyl 2-3. 3-pyridyl 4-methoxyphenyl 2-4. 2-pyrimidyl4-methoxyphenyl 2-5. 2-Cl-phenyl 4-methoxyphenyl 2-6. 2-F-phenyl4-methoxyphenyl 2-7. piperidinyl 4-methoxyphenyl 2-8. phenyl2-aminomethylphenyl 2-9. 2-pyridyl 2-aminomethylphenyl 2-10. 3-pyridyl2-aminomethylphenyl 2-11. 2-pyrimidyl 2-aminomethylphenyl 2-12.2-Cl-phenyl 2-aminomethylphenyl 2-13. 2-F-phenyl 2-aminomethylphenyl2-14. piperidinyl 2-aminomethylphenyl 2-15. phenyl 3-aminomethylphenyl2-16. 2-pyridyl 3-aminomethylphenyl 2-17. 3-pyridyl 3-aminomethylphenyl2-18. 2-pyrimidyl 3-aminomethylphenyl 2-19. 2-Cl-phenyl3-aminomethylphenyl 2-20. 2-F-phenyl 3-aminomethylphenyl 2-21.piperidinyl 3-aminomethylphenyl 2-22. phenyl 2-amidophenyl 2-23.2-pyridyl 2-amidophenyl 2-24. 3-pyridyl 2-amidophenyl 2-25. 2-pyrimidyl2-amidophenyl 2-26. 2-Cl-phenyl 2-amidophenyl 2-27. 2-F-phenyl2-amidophenyl 2-28. piperidinyl 2-amidophenyl 2-29. phenyl2-amido-4-methoxy-phenyl 2-30. 2-pyridyl 2-amido-4-methoxy-phenyl 2-31.3-pyridyl 2-amido-4-methoxy-phenyl 2-32. 2-pyrimidyl2-amido-4-methoxy-phenyl 2-33. 2-Cl-phenyl 2-amido-4-methoxy-phenyl2-34. 2-F-phenyl 2-amido-4-methoxy-phenyl 2-35. piperidinyl2-amido-4-methoxy-phenyl 2-36. phenyl 3-amidophenyl 2-37. 2-pyridyl3-amidophenyl 2-38. 3-pyridyl 3-amidophenyl 2-39. 2-pyrimidyl3-amidophenyl 2-40. 2-Cl-phenyl 3-amidophenyl 2-41. 2-F-phenyl3-amidophenyl 2-42. piperidinyl 3-amidophenyl 2-43. phenyl3-chlorophenyl 2-44. 2-pyridyl 3-chlorophenyl 2-45. 3-pyridyl3-chlorophenyl 2-46. 2-pyrimidyl 3-chlorophenyl 2-47. 2-Cl-phenyl3-chlorophenyl 2-48. 2-F-phenyl 3-chlorophenyl 2-49. piperidinyl3-chlorophenyl 2-50. phenyl 3-amino-4-chloro-phenyl 2-51. 2-pyridyl3-amino-4-chloro-phenyl 2-52. 3-pyridyl 3-amino-4-chloro-phenyl 2-53.2-pyrimidyl 3-amino-4-chloro-phenyl 2-54. 2-Cl-phenyl3-amino-4-chloro-phenyl 2-55. 2-F-phenyl 3-amino-4-chloro-phenyl 2-56.piperidinyl 3-amino-4-chloro-phenyl 2-57. phenyl 2-aminosulfonyl-phenyl2-58. 2-pyridyl 2-aminosulfonyl-phenyl 2-59. 3-pyridyl2-aminosulfonyl-phenyl 2-60. 2-pyrimidyl 2-aminosulfonyl-phenyl 2-61.2-Cl-phenyl 2-aminosulfonyl-phenyl 2-62. 2-F-phenyl2-aminosulfonyl-phenyl 2-63. piperidinyl 2-aminosulfonyl-phenyl 2-64.phenyl 2-aminosulfonyl-4- methoxyphenyl 2-65. 2-pyridyl2-aminosulfonyl-4- methoxyphenyl 2-66. 3-pyridyl 2-aminosulfonyl-4-methoxyphenyl 2-67. 2-pyrimidyl 2 -aminosulfonyl-4- methoxyphenyl 2-68.2-Cl-phenyl 2-aminosulfonyl-4- methoxyphenyl 2-69. 2-F-phenyl2-aminosulfonyl-4- methoxyphenyl 2-70. piperidinyl 2-aminosulfonyl-4-methoxyphenyl 2-71. phenyl 3(1′,2′,4′-triazolin-5′- on-3′-yl)phenyl2-72. 2-pyridyl 3-(1′,2′,4′-triazolin-5′- on-3′-yl)phenyl 2-73.3-pyridyl 3-(1′,2′,4′-triazolin-5′- on-3′-yl)phenyl 2-74. 2-pyrimidyl3-(1′,2′,4′-triazolin-5′- on-3′-yl)phenyl 2-75. 2-Cl-phenyl3-(1′,2′,4′-triazolin-5′- on-3′yl)phenyl 2-76. 2-F-phenyl3-(1′,2′,4′-triazolin-5′- on-3′-yl)phenyl 2-77. piperidinyl3-(1′,2′,4′-triazolin-5′- on-3′-yl)phenyl 2-78. phenyl1-aminoisoquinolin-6-yl 2-79. 2-pyridyl 1-aminoisoquinolin-6-yl 2-80.3-pyridyl 1-aminoisoquinolin-6-yl 2-81. 2-pyrimidyl1-aminoisoquinolin-6-yl 2-82. 2-Cl-phenyl 1-aminoisoquinolin-6-yl 2-83.2-F-phenyl 1-aminoisoquinolin-6-yl 2-84. piperidinyl1-aminoisoquinolin-6-yl 2-85. phenyl 1-aminoisoquinolin-7-yl 2-86.2-pyridyl 1-aminoisoquinolin-7-yl 2-87. 3-pyridyl1-aminoisoquinolin-7-yl 2-88. 2-pyrimidyl 1-aminoisoquinolin-7-yl 2-89.2-Cl-phenyl 1-aminoisoquinolin-7-yl 2-90. 2-F-phenyl1-aminoisoquinolin-7-yl 2-91. piperidinyl 1-aminoisoquinolin-7-yl 2-92.phenyl 4-aminoquinazol-6-yl 2-93. 2-pyridyl 4-aminoquinazol-6-yl 2-94.3-pyridyl 4-aminoquinazol-6-yl 2-95. 2-pyrimidyl 4-aminoquinazol-6-yl2-96. 2-Cl-phenyl 4-aminoquinazol-6-yl 2-97. 2-F-phenyl4-aminoquinazol-6-yl 2-98. piperidinyl 4-aminoquinazol-6-yl 2-99. phenyl4-aminoquinazol-7-yl 2-100. 2-pyridyl 4-aminoquinazol-7-yl 2-101.3-pyridyl 4-aminoquinazol-7-yl 2-102. 2-pyrimidyl 4-aminoquinazol-7-yl2-103. 2-Cl-phenyl 4-aminoquinazol-7-yl 2-104. 2-F-phenyl4-aminoquinazol-7-yl 2-105. piperidinyl 4-aminoquinazol-7-yl 2-106.phenyl 3-aminobenzisoxazol-5-yl 2-107. 2-pyridyl3-aminobenzisoxazol-5-yl 2-108. 3-pyridyl 3-aminobenzisoxazol-5-yl2-109. 2-pyrimidyl 3-aminobenzisoxazol-5-yl 2-110. 2-Cl-phenyl3-aminobenzisoxazol-5-yl 2-111. 2-F-phenyl 3-aminobenzisoxazol-5-yl2-112. piperidinyl 3-aminobenzisoxazol-5-yl 2-113. phenyl3-aminobenzisoxazol-6-yl 2-114. 2-pyridyl 3-aminobenzisoxazol-6-yl2-115. 3-pyridyl 3-aminobenzisoxazol-6-yl 2-116. 2-pyrimidyl3-aminobenzisoxazol-6-yl 2-117. 2-Cl-phenyl 3-aminobenzisoxazol-6-yl2-118. 2-F-phenyl 3-aminobenzisoxazol-6-yl 2-119. piperidinyl3-aminobenzisoxazol-6-yl 2-120. phenyl 3-aminoindazol-5-yl 2-121.2-pyridyl 3-aminoindazol-5-yl 2-122. 3-pyridyl 3-aminoindazol-5-yl2-123. 2-pyrimidyl 3-aminoindazol-5-yl 2-124. 2-Cl-phenyl3-aminoindazol-5-yl 2-125. 2-F-phenyl 3-aminoindazol-5-yl 2-126.piperidinyl 3-aminoindazol-5-yl 2-127. phenyl 3-aminoindazol-6-yl 2-128.2-pyridyl 3-aminoindazol-6-yl 2-129. 3-pyridyl 3-aminoindazol-6-yl2-130. 2-pyrimidyl 3-aminoindazol-6-yl 2-131. 2-Cl-phenyl3-aminoindazol-6-yl 2-132. 2-F-phenyl 3-aminoindazol-6-yl 2-133.piperidinyl 3-aminoindazol-6-yl 2-134. phenyl indolin-5-yl 2-135.2-pyridyl indolin-5-yl 2-136. 3-pyridyl indolin-5-yl 2-137. 2-pyrimidylindolin-5-yl 2-138. 2-Cl-phenyl indolin-5-yl 2-139. 2-F-phenylindolin-5-yl 2-140. piperidinyl indolin-5-yl 2-141. phenyl indolin-6-yl2-142. 2-pyridyl indolin-6-yl 2-143. 3-pyridyl indolin-6-yl 2-144.2-pyrimidyl indolin-6-yl 2-145. 2-Cl-phenyl indolin-6-yl 2-146.2-F-phenyl indolin-6-yl 2-147. piperidinyl indolin-6-yl 2-148. phenyl2-naphthyl 2-149. 2-pyridyl 2-naphthyl 2-150. 3-pyridyl 2-naphthyl2-151. 2-pyrimidyl 2-naphthyl 2-152. 2-Cl-phenyl 2-naphthyl 2-153.2-F-phenyl 2-naphthyl 2-154. piperidinyl 2-naphthyl 2-155. phenyl3-amido-naphth-2-yl 2-156. 2-pyridyl 3-amido-naphth-2-yl 2-157.3-pyridyl 3-amido-naphth-2-yl 2-158. 2-pyrimidyl 3-amido-naphth-2-yl2-159. 2-Cl-phenyl 3-amido-naphth-2-yl 2-160. 2-F-phenyl3-amido-naphth-2-yl 2-161. piperidinyl 3-amido-naphth-2-yl 2-162. phenyl3-methylsulfonyl-naphth-2- yl 2-163. 2-pyridyl3-methylsulfonyl-naphth-2- yl 2-164. 3-pyridyl3-methylsulfonyl-naphth-2- yl 2-165. 2-pyrimidyl3-methylsulfonyl-naphth-2- yl 2-166. 2-Cl-phenyl3-methylsulfonyl-naphth-2- yl 2-167. 2-F-phenyl3-methylsulfonyl-naphth-2- yl 2-168. piperidinyl3-methylsulfonyl-naphth-2- yl 2-169. phenyl 3-aminomethyl-naphth-2-yl2-170. 2-pyridyl 3-aminomethyl-naphth-2-yl 2-171. 3-pyridyl3-aminomethyl-naphth-2-yl 2-172. 2-pyrimidyl 3-aminomethyl-naphth-2-yl2-173. 2-Cl-phenyl 3-aminomethyl-naphth-2-yl 2-174. 2-F-phenyl3-aminomethyl-naphth-2-yl 2-175. piperidinyl 3-aminomethyl-naphth-2-yl2-176. phenyl 3-fluoro-naphth-2-yl 2-177. 2-pyridyl 3-fluoro-naphth-2-yl2-178. 3-pyridyl 3-fluoro-naphth-2-yl 2-179. 2-pyrimidyl3-fluoro-naphth-2-yl 2-180. 2-Cl-phenyl 3-fluoro-naphth-2-yl 2-181.2-F-phenyl 3-fluoro-naphth-2-yl 2-182. Piperidinyl 3-fluoro-naphth-2-yl2-183. phenyl 3-cyano-naphth-2-yl 2-184. 2-pyridyl 3-cyano-naphth-2-yl2-185. 3-pyridyl 3-cyano-naphth-2-yl 2-186. 2-pyrimidyl3-cyano-naphth-2-yl 2-187. 2-Cl-phenyl 3-cyano-naphth-2-yl 2-188.2-F-phenyl 3-cyano-naphth-2-yl 2-189. Piperidinyl 3-cyano-naphth-2-yl2-190. phenyl 3-aminosulfonyl-naphth-2-yl 2-191. 2-pyridyl3-aminosulfonyl-naphth-2-yl 2-192. 3-pyridyl 3-aminosulfonyl-naphth-2-yl2-193. 2-pyrimidyl 3-aminosulfonyl-naphth-2-yl 2-194. 2-Cl-phenyl3-aminosulfonyl-naphth-2-yl 2-195. 2-F-phenyl3-aminosulfonyl-naphth-2-yl 2-196. piperidinyl3-aminosulfonyl-naphth-2-yl 2-197. phenyl 6-chloro-naphth-2-yl 2-198.2-pyridyl 6-chloro-naphth-2-yl 2-199. 3-pyridyl 6-chloro-naphth-2-yl2-200. 2-pyrimidyl 6-chloro-naphth-2-yl 2-201. 2-Cl-phenyl6-chloro-naphth-2-yl 2-202. 2-F-phenyl 6-chloro-naphth-2-yl 2-203.Piperidinyl 6-chloro-naphth-2-yl

TABLE 3 Examples 3-1-through 3-6090 use the structures from Table 2 andthe corresponding A and G groups from Examples 1-203 of Table 2:Examples 3-1 to 3-203, R^(1a) is CH₂CH₃; Examples 3-204 to 3-406, R^(1a)is CF₃; Examples 3-407 to 3-609, R^(1a) is SCH₃; Examples 3-610 to3-812, R^(1a) is SOCH₃; Examples 3-813 to 3-1015, R^(1a) is SO₂CH₃;Examples 3-1016 to 3-1218, R^(1a) is Cl; Examples 3-1219 to 3-1421,R^(1a) is F; Examples 3-1422 to 3-1624, R^(1a) is CO₂CH₃; Examples3-1625 to 3-1827, R^(1a) is CH₂OCH₃; Examples 3-1828 to 3-2030, R^(1a)is CONH₂; Examples 3-2031 to 3-2233, R^(1a) is —CN; Examples 3-2234 to3-2436, R^(1a) is CH₂NHCH₃; Examples 3-2437 to 3-2639, R^(1a) isCH₂NHSO₂CH₃; Examples 3-2640 to 3-2842, R^(1a) is 1-imidazolyl-CH₂;Examples 3-2843 to 3-3045, R^(1a) is Br; Examples 3-3046 to 3-3248,R^(1a) is 5-tetrazolyl; Examples 3-3249 to 3-3451, R^(1a) is N(CH₃)₂;Examples 3-3452 to 3-3654, R^(1a) is NHCH₃; Examples 3-3655 to 3-3857,R^(1a) is SO₂NH₂; Examples 3-3858 to 3-4060, R^(1a) is 2-pyridine;Examples 3-4061 to 3-4263, R^(1a) is 3-pyridine; Examples 3-4264 to3-4466, R^(1a) is 4-pyridine; Examples 3-4467 to 3-4872, R^(1a) is2-pyridine-N-oxide; Examples 3-4873 to 3-5075, R^(1a) is3-pyridine-N-oxide; Examples 3-5076 to 3-5287, R^(1a) is4-pyridine-N-oxide; Examples 3-5288 to 3-5481, R^(1a) is OCH₃; Examples3-5482 to 3-5684, R^(1a) is CH₂OC(O)NHCH₃; Examples 3-5685 to 3-5887,R^(1a) is CH₂NHCO₂CH₃; Examples 3-5888 to 3-6090, R^(1a) isCH₂NHC(O)NHCH₃; and, Examples 3-6091 to 3-6293, R^(1a) is H.

TABLE 4

Ex# G 4-1. 4-methoxyphenyl 4-2. 2-aminomethylphenyl 4-3.3-aminomethylphenyl 4-4. 2-amidophenyl 4-5. 2-amido-4-methoxy-phenyl4-6. 3-amidophenyl 4-7. 3-chlorophenyl 4-8. 3-amino-4-chloro-phenyl 4-9.2-aminosulfonyl-phenyl 4-10. 2-aminosulfonyl-4-methoxyphenyl 4-11.3(1′,2′,4′-triazolin-5′-on-3′- yl)phenyl 4-12. 1-aminoisoquinolin-6-yl4-13. 1-aminoisoquinolin-7-yl 4-14. 4-aminoquinazol-6-yl 4-15.4-aminoquinazol-7-yl 4-16. 3-aminobenzisoxazol-5-yl 4-17.3-aminobenzisoxazol-6-yl 4-18. 3-aminoindazol-5-yl 4-19.3-aminoindazol-6-yl 4-20. indolin-5-yl 4-21. indolin-6-yl 4-22.2-naphthyl 4-23. 3-amido-naphth-2-yl 4-24. 3-methylsulfonyl-naphth-2-yl4-25. 3-aminomethyl-naphth-2-yl 4-26. 3-fluoro-naphth-2-yl 4-27.3-chloro-naphth-2-yl 4-28. 3-aminosulfonyl-naphth-2-yl 4-29.6-chloro-naphth-2-yl

TABLE 5

Ex# R^(1a) G 5-1. CH₃ 4-methoxyphenyl 5-2. CH₂CH₃ 4-methoxyphenyl 5-3.CF₃ 4-methoxyphenyl 5-4. SCH₃ 4-methoxyphenyl 5-5. SOCH₃ 4-methoxyphenyl5-6. SO₂CH₃ 4-methoxyphenyl 5-7. Cl 4-methoxyphenyl 5-8. F4-methoxyphenyl 5-9. CO₂CH₃ 4-methoxyphenyl 5-10. CH₂OCH₃4-methoxyphenyl 5-11. CONH₂ 4-methoxyphenyl 5-12. CN 4-methoxyphenyl5-13. CH₂NH₂ 4-methoxyphenyl 5-14. CH₂NHSO₂CH₃ 4-methoxyphenyl 5-15.1-imidazolyl-CH₂ 4-methoxyphenyl 5-16. 1-tetrazolyl-CH₂— 4-methoxyphenyl5-17. Br 4-methoxyphenyl 5-18. 5-tetrazolyl 4-methoxyphenyl 5-19.N(CH₃)₂ 4-methoxyphenyl 5-20. NHCH₃ 4-methoxyphenyl 5-21. SO₂NH₂4-methoxyphenyl 5-22. 2-pyridine 4-methoxyphenyl 5-23. 3-pyridine4-methoxyphenyl 5-24. 4-pyridine 4-methoxyphenyl 5-25.2-pyridine-N-oxide 4-methoxyphenyl 5-26. 3-pyridine-N-oxide4-methoxyphenyl 5-27. 4-pyridine-N-oxide 4-methoxyphenyl 5-28. OCH₃4-methoxyphenyl 5-29. CH₂OC(O)NHCH₃ 4-methoxyphenyl 5-30. CH₂NHCO₂CH₃4-methoxyphenyl 5-31. CH₂NHC(O)NHCH₃ 4-methoxyphenyl 5-32. H4-methoxyphenyl

For Examples 5-33 through 5-64, G is 2-aminomethylphenyl and R^(1a) isas shown in Examples 5-1 through 5-32.

For Examples 5-65 through 5-96, G is 3-aminomethylphenyl and R^(1a) isas shown in Examples 5-1 through 5-32.

For Examples 5-97 through 5-128, G is 2-amidophenyl and R^(1a) is asshown in Examples 5-1 through 5-32.

For Examples 5-129 through 5-160, G is 2-amido-4-methoxyphenyl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-161 through 5-192, G is 3-amidophenyl and R^(1a) is asshown in Examples 5-1 through 5-32.

For Examples 5-193 through 5-224, G is 3-chlorophenyl and R^(1a) is asshown in Examples 5-1 through 5-32.

For Examples 5-225 through 5-256, G is 3-amino-4-chlorophenyl and R^(1a)is as shown in Examples 5-1 through 5-32.

For Examples 5-257 through 5-288, G is 2-aminosulfonylphenyl and R^(1a)is as shown in Examples 5-1 through 5-32.

For Examples 5-289 through 5-320, G is 2-aminosulfonyl-4-methoxyphenyland R^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-321 through 5-352, G is3-(1′,2′,4′-triazolin-5′-on-3′-yl)phenyl and R^(1a) is as shown inExamples 5-1 through 5-32.

For Examples 5-353 through 5-384, G is 1-aminoisoquinolin-6-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-385 through 5-416, G is 1-aminoisoquinolin-7-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-417 through 5-448, G is 4-aminoquinazol-6-yl and R^(1a)is as shown in Examples 5-1 through 5-32.

For Examples 5-449 through 5-480, G is 4-aminoquinazol-7-yl and R^(1a)is as shown in Examples 5-1 through 5-32.

For Examples 5-481 through 5-512, G is 3-aminobenzisoxazol-5-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-513 through 5-544, G is 3-aminobenzisoxazol-6-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-545 through 5-576, G is 3-aminoindazol-5-yl and R^(1a) isas shown in Examples 5-1 through 5-32.

For Examples 5-577 through 5-608, G is 3-aminoindazol-6-yl and R^(1a) isas shown in Examples 5-1 through 5-32.

For Examples 5-609 through 5-640, G is indolin-5-yl and R^(1a) is asshown in Examples 5-1 through 5-32.

For Examples 5-641 through 5-672, G is indolin-6-yl and R^(1a) is asshown in Examples 5-1 through 5-32.

For Examples 5-673 through 5-704, G is 2-naphthyl and R^(1a) is as shownin Examples 5-1 through 5-32.

For Examples 5-705 through 5-736, G is 3-amido-naphth-2-yl and R^(1a) isas shown in Examples 5-1 through 5-32.

For Examples 5-737 through 5-768, G is 3-methylsulfonyl-naphth-2-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-769 through 5-800, G is 3-aminomethyl-naphth-2-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-801 through 5-832, G is 3-flouro-naphth-2-yl and R^(1a)is as shown in Examples 5-1 through 5-32.

For Examples 5-833 through 5-864, G is 3-chloro-naphth-2-yl and R^(1a)is as shown in Examples 5-1 through 5-32.

For Examples 5-865 through 5-896, G is 3-aminosulfonyl-naphth-2-yl andR^(1a) is as shown in Examples 5-1 through 5-32.

For Examples 5-897 through 5-928, G is 6-chloro-naphth-2-yl and R^(1a)is as shown in Examples 5-1 through 5-32.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A compound of3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-oneor a pharmaceutically acceptable salt form thereof.
 2. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.
 3. A method for treatinga thromboembolic disorder, comprising: administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt form thereof.
 4. A methodaccording to claim 3, wherein the thromboembolic disorder is selectedfrom the group consisting of arterial cardiovascular thromboembolicdisorders, venous cardiovascular thromboembolic disorders, andthromboembolic disorders in the chambers of the heart.
 5. A methodaccording to claim 3, wherein the thromboembolic disorder is selectedfrom unstable angina, an acute coronary syndrome, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from (a) prosthetic valvesor other implants, (b) indwelling catheters, (c) stents, (d)cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.
 6. A method according to claim 5, wherein the thromboembolicdisorder is an acute coronary syndrome.
 7. A method according to claim5, wherein the thromboembolic disorder is stroke.
 8. A method accordingto claim 5, wherein the thromboembolic disorder is deep vein thrombosis.9. A method according to claim 5, wherein the thromboembolic disorder ispulmonary embolism.